Mélanie Kremer

Léa J Becker

PhD Michel Barrot
email: mbarrot@inci-cnrs.unistra.fr

PhD Ipek Yalcin
email: yalcin@unistra.fr

How to study anxiety and depression in rodent models of chronic pain? Running Title: Anxiodepressive-like consequences of chronic pain

Keywords: depression, anxiety, pain, models, tests Anterior Cingulate Cortex, BT: Burrowing Test, CCI: Chronic Constriction Injury: CeA: Central Nucleus of the Amygdala, CFA: Complete Freund's Adjuvant, CION: Infraorbital Nerve Constriction, DM3T: Dimethyl-3-transferase, EPM: Elevated Plus Maze, EZM: Elevated Indoleamine 2,3-dioxygenase 1 Trigeminal Inflammatory Compression, TNF: Tumor Necrosis Factor, TNT: Tibial Nerve Transection

Mood disorders such as depression and anxiety are frequently observed in patients suffering from chronic pain. Over time, different tests and models have been developed in rodents to study the anxiodepressive-like consequences of chronic pain. This review describes these pre-clinical tools (models and tests) used for studying behavioural aspects of the comorbid relationship between chronic pain and anxiety and/or major depressive disorder (MDD). Three major types of chronic pain strongly associated with anxiodepressive-like comorbidity as well as their animal models are presented: neuropathic pain, inflammatory pain and fibromyalgia. After a description of chronic pain animal models and of the tests that allows determining nociceptive responses, this review presents and discusses the various behavioural tests that have been used to assess anxiety and depressive-like behaviours in these models of chronic pain. Finally, this review highlights the progress that remains to be made to homogenize the results in the field of pain-induced mood disorders and summarizes the recent advances achieved through these tests and models.

Introduction

Pain is a multidimensional and subjective experience which is considered as a debilitating disease when it becomes chronic. Chronic pain does indeed affect various aspects of the patient's quality of life, including mood, sleep and cognitive processes [START_REF] Maletic | Neurobiology of depression, fibromyalgia and neuropathic pain[END_REF]Haanpaa et al., 2011;Radat et al., 2013). In chronic pain patients, mood disorders such as major depressive disorders and anxiety are frequently observed [START_REF] Bair | Depression and pain comorbidity: a literature review[END_REF]Gustorff et al., 2008;[START_REF] Maletic | Neurobiology of depression, fibromyalgia and neuropathic pain[END_REF]Radat et al., 2013).

Major depressive disorders are highly disabling psychiatric disorder which affects around 16% of the population at some point over their lifespan (Bromet et al., 2011) and is among the main contributors to the disease burden worldwide [START_REF] Kessler | The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R)[END_REF][START_REF] Olesen | The economic cost of brain disorders in Europe[END_REF]. Due to its multifactorial nature and heterogeneous symptomatology, the precise aetiology of this debilitating disorder remains poorly understood [START_REF] Menard | Pathogenesis of depression: Insights from human and rodent studies[END_REF]. However, besides chronic stress and psychosocial trauma [START_REF] Liu | Stress generation in depression: A systematic review of the empirical literature and recommendations for future study[END_REF], chronic pain can also be cited among the first determinants of mood disorders [START_REF] Mcwilliams | Depression and anxiety associated with three pain conditions: results from a nationally representative sample[END_REF][START_REF] Breivik | Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment[END_REF][START_REF] Attal | The specific disease burden of neuropathic pain: results of a French nationwide survey[END_REF], as shown by the mean prevalence rate around 50% for major depressive disorder reported in these patients [START_REF] Bair | Depression and pain comorbidity: a literature review[END_REF]. Besides, anxiety is also among mood disorders frequently diagnosed in chronic pain patients. Indeed, this psychopathology, defined by excessive fear and worry, affects up to 60% of chronic pain patients. This prevalence is however highly dependent on the considered type of pain, with the lowest rate (between 1 and 27%) for neuropathic pain and the highest (between 18 and 60%) for fibromyalgia [START_REF] Hooten | Chronic Pain and Mental Health Disorders: Shared Neural Mechanisms, Epidemiology, and Treatment[END_REF].

Different models have been developed in rodents to study the various types of clinically observed chronic pain conditions [START_REF] Mogil | Animal models of pain: progress and challenges[END_REF][START_REF] Jaggi | Animal models of neuropathic pain[END_REF][START_REF] Muley | Preclinical Assessment of Inflammatory Pain[END_REF]Sluka & Clauw, 2016;Fischer et al., 2017;[START_REF] Kumar | Neuropathic Pain models caused by damage to central or peripheral nervous system[END_REF], as well as their anxiodepressive consequences [START_REF] Liu | Preclinical research on pain comorbidity with affective disorders and cognitive deficits: Challenges and perspectives[END_REF][START_REF] Leite-Almeida | Animal Models for the Study of Comorbid Pain and Psychiatric Disorders[END_REF]. While several groups successfully achieved to model this comorbidity in animals (Narita et al., 2006a;Narita et al., 2006b;Suzuki et al., 2007;Goncalves et al., 2008;[START_REF] Matsuzawa-Yanagida | Usefulness of Accepted Article This article is protected by copyright. All rights reserved antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites[END_REF], many initial studies and some of the recent ones failed to show any association between chronic neuropathic or inflammatory pain and anxiety-and depression-related behaviours [START_REF] Kontinen | Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy[END_REF]Hasnie et al., 2007b;Urban et al., 2011;[START_REF] Pitzer | Inflammatory and neuropathic pain conditions do not primarily evoke anxiety-like behaviours in C57BL/6 mice[END_REF]. However, some of the negative studies (but not all) were done at early pain stages, i.e. during the first week or the first 3 weeks following inflammatory and neuropathy induction, respectively. While it may not be the only aspect that allows explaining the presence or not of anxiodepressive-like consequences in rodent models of

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This article is protected by copyright. All rights reserved chronic pain, the time factor appears as critical [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF]Yalcin & Barrot, 2014;[START_REF] Humo | The molecular neurobiology of chronic pain-induced depression[END_REF]. Others factors, such as the species, the strains of animals, the chosen models of chronic pain, and the time of the day-night cycle when the animals are tested, could also be involved.

In this review, based on the literature up to December 2019, we summarized the pre-clinical tools (models and tests) used over the past two decades and pertaining to behavioural aspects of the comorbid relationship between chronic pain and anxiety and/or major depressive disorder (MDD). After a brief description of the types of chronic pain and of their animal models, as well as the tests that allow determining nociceptive responses, we will present and discuss the various behavioural tests that have been used to assess anxiety and depressive-like behaviours in these models of chronic pain.

Animal models of pain that have been used in research on anxiety and/or depression

Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Acting as an alarm signal, acute pain triggers reactions to preserve the integrity of the organism [START_REF] Scholz | Can we conquer pain?[END_REF][START_REF] Morrison | Facets and mechanisms of adaptive pain behavior: predictive regulation and action[END_REF]. When pain persists beyond several months, it is considered as chronic. Contrary to acute pain, chronic pain is regarded as an illness per se, and mood disorders are among its comorbidities [START_REF] Attal | The specific disease burden of neuropathic pain: results of a French nationwide survey[END_REF]Haanpaa et al., 2011). According to the epidemiological studies the prevalence rate of major depressive disorder in patients with chronic pain [START_REF] Bair | Depression and pain comorbidity: a literature review[END_REF][START_REF] Maletic | Neurobiology of depression, fibromyalgia and neuropathic pain[END_REF] varies from around 30% for patients suffering from neuropathic pain (Gustorff et al., 2008;Radat et al., 2013), to around 80% in fibromyalgia patients (Fietta et al., 2007). Up to recently, the mechanism(s) underlying this comorbidity remained unclear (Yalcin & Barrot, 2014;Doan et al., 2015;Fasick et al., 2015;Zis et al., 2017). However, main advances have been achieved in the past decade, thanks to the development of animal models that allow studying anxiodepressive consequences of chronic pain (Yalcin & Barrot, 2014;[START_REF] Leite-Almeida | Animal Models for the Study of Comorbid Pain and Psychiatric Disorders[END_REF]. We will focus here three major types of chronic pain strongly associated with anxiodepressive-like comorbidity: neuropathic pain, inflammatory pain and fibromyalgia.

Neuropathic pain and its animal models

By definition, neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system [START_REF] Roeska | Anxiety-like behaviour in rats with mononeuropathy is reduced by the analgesic drugs morphine and gabapentin[END_REF]. It is a syndrome usually chronic, with various

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This article is protected by copyright. All rights reserved possible aetiologies. For most patients it has a peripheral origin, arising as a consequence of peripheral nerve injury (nerve section or compression), or as a consequence of a metabolic disease such as diabetes. Nerve injuries and diabetic peripheral neuropathy account for almost two-thirds of the patients. However, neuropathic pain can also result from infectious diseases, as in postherpetic neuralgia, from exposure to neurotoxic compounds, such as those used for cancer chemotherapy, or be of central origin, as observed after spinal cord injury or local post-stroke ischemia [START_REF] Attal | Neuropathic pain: are there distinct subtypes depending on the aetiology or anatomical lesion[END_REF][START_REF] Colloca | Neuropathic pain[END_REF]Zilliox, 2017;[START_REF] Scholz | The IASP classification of chronic pain for ICD-11: chronic neuropathic pain[END_REF].

A large number of animal models of neuropathic pain has been developed (Sorkin & Yaksh, 2009;[START_REF] Colleoni | Murine models of human neuropathic pain[END_REF][START_REF] Jaggi | Animal models of neuropathic pain[END_REF][START_REF] Kumar | Neuropathic Pain models caused by damage to central or peripheral nervous system[END_REF], but their exhaustive presentation is beyond the scope of this review. Here, we will simply focus on the few models in which most of the comorbidity studies on anxiodepressive aspects were performed. Almost 90% of the published studies used trauma models based on chronic nerve compression (see Figure 1). This nerve compression has been achieved either by ligation, as for the partial sciatic nerve ligation (PSNL) which is a tight ligation of one-third to half of the sciatic nerve [START_REF] Seltzer | A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury[END_REF], the spinal nerve ligation (SNL) which is a tight ligation of L5 and L6 spinal nerves [START_REF] Kim | An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat[END_REF] or of L5 spinal nerve only [START_REF] Labuda | Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat[END_REF], the chronic constriction injury (CCI) consisting in four loose ligatures applied around the sciatic nerve [START_REF] Bennett | A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man[END_REF], or by the implantation of a polyethylene cuff around the main branch of the sciatic nerve [START_REF] Mosconi | Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations[END_REF]. Another frequently used trauma model is the spared nerve injury (SNI), which relies on the axotomy of two of the three branches of the sciatic nerve [START_REF] Decosterd | Spared nerve injury: an animal model of persistent peripheral neuropathic pain[END_REF].

The tibial nerve transection (TNT) is a variant of this model in which the axotomy concerns the tibial nerve only [START_REF] Andrews | Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain[END_REF]. The anxiodepressive comorbidity has also been studied using trigeminal neuralgia models, such as the infraorbital nerve constriction (CION) which corresponds to CCI of the infraorbital nerve (Vos et al., 1994), or in animals with trigeminal inflammatory compression (TIC) induced by a chromic gut suture alongside the infraorbital nerve [START_REF] Ma | Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve[END_REF].

Beside nerve lesion, diseases affecting the somatosensory system constitute another main aetiology of neuropathic pain (Jolivalt et al., 2016). In this regard, anxiodepressive-like comorbidities have also been studied in a streptozotocin model, which is a common model of diabetic polyneuropathy [START_REF] Lenzen | The mechanisms of alloxan-and streptozotocin-induced diabetes[END_REF], and in models of human immunodeficiency virus (HIV) 1 protein gp120 (Wallace et al., 2007b) or zoster varicella virus (Hasnie et al., 2007a) as infection models. Exposure to neurotoxic drugs, such as the HIV antiretroviral stavudine (Joseph et al.,

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This article is protected by copyright. All rights reserved 2004) or the chemotherapy drugs oxaliplatin [START_REF] Cavaletti | Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat[END_REF] or paclitaxel [START_REF] Cavaletti | Experimental peripheral neuropathy induced in adult rats by repeated intraperitoneal administration of taxol[END_REF], have also been used to study the comorbidity between neuropathic pain and anxiety/depressive-like behaviours.

Concerning central neuropathies, studies of anxiety/depressive-like behaviours have been done using a model of spinal cord injury (SCI) induced by dropping a weight over the exposed spinal cord [START_REF] Behrmann | Spinal cord injury produced by consistent mechanical displacement of the cord in rats: behavioral and histologic analysis[END_REF], or by using a photochemical reaction to form a thrombosis and occlusion in small vessels supplying the spinal cord (Verdu et al., 2003).

Inflammatory pain and its animal models

When inflammation becomes chronic, it loses its role as natural physiological response to tissue injury or infection, and it becomes a maladaptive and physiopathological condition. The chemical mediators that are responsible for tissue inflammation affect nociceptive nerve endings to lower neuronal excitation thresholds and sensitize afferent firing rate, leading to the development of allodynia and hyperalgesia, respectively [START_REF] Kidd | Mechanisms of inflammatory pain[END_REF][START_REF] Lipnik-Stangelj | Mediators of inflammation as targets for chronic pain treatment[END_REF]. One of the main organ systems that is particularly susceptible to the development of inflammatory pain is joints.

Arthritis, which literally means joint inflammation, refers to a group of rheumatic diseases and other conditions that can cause pain, stiffness and swelling in the joints. It includes forms ranging from those related to wear and tear of cartilage (such as osteoarthritis [START_REF] Kuyinu | Animal models of osteoarthritis: classification, update, and measurement of outcomes[END_REF]), to those associated with inflammation resulting from an overactive immune system (such as rheumatoid arthritis) [START_REF] Di Paola | Predictivity and sensitivity of animal models of arthritis[END_REF]. Recent surveys report that rheumatoid arthritis is one of the most common chronic inflammatory pain conditions in developed countries, affecting approximately 15 million people worldwide (Fiest et al., 2017). Rheumatoid arthritis is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue [START_REF] Scott | Rheumatoid arthritis[END_REF]. The pathogenesis of rheumatoid arthritis is complex and involves genetic predispositions as well as environmental factors [START_REF] Imboden | The immunopathogenesis of rheumatoid arthritis[END_REF]. Psychiatric disorders are highly associated with rheumatoid arthritis [START_REF] Nerurkar | Rheumatoid arthritis and depression: an inflammatory perspective[END_REF]. Depression is diagnosed in up to 66% and anxiety in up to 70% of individuals with rheumatoid arthritis (Fiest et al., 2017).

Animal models have contributed to improve our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and its associated comorbidities [START_REF] Kuyinu | Animal models of osteoarthritis: classification, update, and measurement of outcomes[END_REF][START_REF] Muley | Preclinical Assessment of Inflammatory Pain[END_REF]Fischer et al., 2017). The most widely used model for studying the comorbidity between inflammatory pain and anxiodepressive-like disorders

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This article is protected by copyright. All rights reserved has been the complete Freund's adjuvant (CFA)-induced inflammation of the paw (Fehrenbacher et al., 2012). This model is based on a unilateral intraplantar injection of CFA, which can produce a long-lasting (> 3 weeks) decrease in mechanical and thermal thresholds compared to the contralateral non-inflamed paw [START_REF] Cook | Effects of sex, hindpaw injection site and stimulus modality on nociceptive sensitivity in arthritic rats[END_REF]. Carrageenan can also be injected into the paw to model arthritis, but this model is more acute than chronic because the associated mechanical and thermal hypersensitivity usually lasts no longer than 72 hours [START_REF] Mert | Pain-relieving effects of pulsed magnetic fields in a rat model of carrageenan-induced hindpaw inflammation[END_REF].

Monoarthritis models have also been used, by injecting an inflammatory agent such as CFA, uric acid or a kaolin-carrageenan mix directly into the tibiotarsal [START_REF] Butler | A limited arthritic model for chronic pain studies in the rat[END_REF], knee [START_REF] Lopez-Munoz | Analgesic effects of multiple combinations of morphine and aspirin in the rat[END_REF][START_REF] Radhakrishnan | Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats[END_REF] or temporomandibular [START_REF] Harper | Modulation of the inflammatory response in the rat TMJ with increasing doses of complete Freund's adjuvant[END_REF] joint. Obesity is also a main risk factor for the development of arthritis (Georgiev & Angelov, 2019), and a model of arthritis based on dietary obesity (Silberberg & Silberberg, 1950) has also been used to test anxiodepressive-like aspects (Griffin et al., 2010).

Fibromyalgia and its animal models

Fibromyalgia is a condition characterized by chronic widespread musculoskeletal pain, which includes widespread tenderness to pressure stimuli and morning stiffness [START_REF] Clauw | Fibromyalgia: a clinical review[END_REF][START_REF] Hauser | Fibromyalgia[END_REF]Sluka & Clauw, 2016). The pathogenesis of fibromyalgia is complex and controversial, but some recent advances in the field showed the possible involvement of lipid mediators [START_REF] Hsu | ASIC3-dependent metabolomics profiling of serum and urine in a mouse model of fibromyalgia[END_REF], autoimmunity, neuroinflammation and small fiber neuropathy [START_REF] Ryabkova | Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination[END_REF].

There is however no evidence of any single event causing this condition; instead, it is considered to be triggered or aggravated by multiple physical and/or emotional stressors, such as infections, or emotional and physical trauma [START_REF] Schmidt-Wilcke | Fibromyalgia: from pathophysiology to therapy[END_REF]Sluka & Clauw, 2016).

Fibromyalgia is more common in women than in men, and its worldwide prevalence is 2 to 3% [START_REF] Cabo-Meseguer | Fibromyalgia: Prevalence, epidemiologic profiles and economic costs[END_REF]. Fibromyalgia is also associated with a number of other symptoms, including pronounced fatigue, sleep disturbances and psychological disturbances (depression and/or anxiety) [START_REF] Hauser | Fibromyalgia[END_REF]. Overall depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence rates ranging from 20-80% and 13-64% respectively [START_REF] Maletic | Neurobiology of depression, fibromyalgia and neuropathic pain[END_REF]. Some studies tried to address the anxiodepressive consequences in animal models of fibromyalgia. However, as there is no well-defined aetiology of fibromyalgia, the validity of animal models remains imperfect and simply based on symptoms and on the response to treatment (mostly antidepressant drugs). The most frequently used fibromyalgia model addressing depression-like behaviours is based on biogenic amine depletion by systemic reserpine

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This article is protected by copyright. All rights reserved administration [START_REF] Nagakura | Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia[END_REF]. However, the chronic widespread musculoskeletal pain model induced by repeated intramuscular acid injections in rodents has been suggested to have better face validity to human's conditions, but few studies have dealt with the anxiodepressive consequences in this model yet (Liu et al., 2014). Anxiodepressive consequences have also been described in stress-induced fibromyalgia models, such as the cold stress models, i.e intermittent (ICS) [START_REF] Nishiyori | Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia[END_REF] or repeated cold stress (RCS) [START_REF] Nasu | A single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress[END_REF], the unpredictable sound stress model [START_REF] Khasar | Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain[END_REF], or the subchronic swim stress inducing chronic widespread-like pain [START_REF] Nazeri | Evidence of Altered Trigeminal Nociception in an Animal Model of Fibromyalgia[END_REF]. Although existing models mimic some symptoms of fibromyalgia, it is still critical to develop new models which can reflect the different aspects of this syndrome.

Nociceptive tests frequently used to evaluate chronic pain

An important notion in the field of pain is the distinction between pain and nociception. If nociception corresponds to "neural process of encoding noxious stimuli" (i.e. stimuli presenting a risk for the integrity of the body) [START_REF] Basbaum | The perception of pain[END_REF], pain is defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (Box 1) [START_REF] Loeser | Pain: an overview[END_REF][START_REF] Basbaum | Cellular and molecular mechanisms of pain[END_REF][START_REF] Baliki | Nociception, Pain, Negative Moods, and Behavior Selection[END_REF][START_REF] Apkarian | Peripheral and central viewpoints of chronic pain, and translational implications[END_REF]. These two facets of the same phenomenon distinguish the sensation (nociception) from its interpretation (pain). In patients, pain is evaluated verbally, which is not possible in rodents. Thus, rodent "pain tests" are actually nociceptive tests, based on reflex responses, and the preclinical measurement of pain itself is still a challenge for this field of research [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. For a long time, fundamental research on pain and its preclinical treatments has been based on nociceptive tests performed on naive animals, i.e. not painful [START_REF] Bars | Animal models of nociception[END_REF]. But in the past decades, the combination of nociceptive tests and pain models has improved the relevance of studies in the field of pain research [START_REF] Mogil | Animal models of pain: progress and challenges[END_REF].

The main nociceptive tests used in animal studies addressing the comorbidity between pain and anxiodepressive-like disorders are based on thermal or mechanical stimuli [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Leite-Almeida | Animal Models for the Study of Comorbid Pain and Psychiatric Disorders[END_REF]. Some of them, like the tail-flick test, the hot-or cold-plate tests and the radiant heat paw-withdrawal test, rely on the latency for avoidance behaviour: a withdrawal reflex of the paw or the tail [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. Here, the stimulus may be considered as fixed. The tail withdrawal test, the first developed [START_REF] D'amour | A method for determining loss of pain sensation[END_REF], is based on the latency of the withdrawal reflex after applying a heat beam at the end of the tail or

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This article is protected by copyright. All rights reserved after having immersed it in a bath at fixed temperature. Although the observed response results from a spinal reflex, it remains under the influence of supraspinal controls as well as mechanisms of thermoregulation [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF]. This test, sensitive to opiates, has been used extensively for analgesic research. Nevertheless, this test is much less used in models of chronic pain such as inflammatory pain or trauma models of neuropathic pain since these models rather focus on one of the paws of the animal. The hot-plate [START_REF] Woolfe | The evaluation of the analgesic action of pethidine hydrochloride (Demerol)[END_REF]O'Callaghan & Holtzman, 1975) is another classic test developed in the 1940s, most often with a plate temperature set at 52 or 55°C for rodents. These temperatures, which are 10 to 15°C higher than the nociceptor response thresholds, are necessary for the increase in skin temperature to activate the nociceptors and thus to observe a supraspinal response within less than 10 seconds. The measurement is most often the latency of withdrawal and licking of the paw, but in the mouse the jump of the animal is sometimes taken into consideration [START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF] [START_REF] Hargreaves | A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia[END_REF][START_REF] Muley | Preclinical Assessment of Inflammatory Pain[END_REF]. The animal is placed on a glass floor and the point source of heat is brought under the paw to be tested, the system automatically detects the withdrawal of the paw. This test is useful in unilateral pain models, like most models of inflammatory and neuropathic pain. Similarly, the cold nociceptive response can be tested using a cold-plate test [START_REF] Bennett | A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man[END_REF][START_REF] Choi | Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain[END_REF], but this measure can be more difficult to establish as the response latency is sometimes unreliable, and the number of responses over a given period of time is generally preferred [START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF].

Finally, some of the thermal nociceptive tests are based on the observation and quantification of nociceptive behaviours, as is the case with the acetone test. To assess cold allodynia, a drop of acetone can be applied on the hind paws [START_REF] Choi | Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain[END_REF]. Its evaporation produces a cold stimulus, which is usually not detected as nociceptive by naive animals but results in cold allodynia in pain models [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF].

Other nociceptive tests, such as the von Frey filaments or the Randall-Selitto analgesimeter, can rely on the mechanical stimulus threshold necessary to elicit an avoidance behaviour [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Muley | Preclinical Assessment of Inflammatory Pain[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. In this case, the stimulus is variable with increasing value. An advantage of these tests is to measure allodynia, i.e. the response to a normally nonnociceptive stimulus, or hyperalgesia, an exaggerated response to a nociceptive stimulus. While all mechanical tests are feasible in rats, the von Frey test mostly remains preferred in mice. These filaments of various diameters are generally applied to the plantar surface, until they bend exerting

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This article is protected by copyright. All rights reserved a calibrated pressure. The threshold filament inducing a response gives the value of the mechanical sensitivity threshold. This value is nevertheless influenced by the speed and the duration of application of the filaments, and the standardization of the procedure is therefore particularly important [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF]. In recent years, automated versions of this test have been developed [START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. Manual or motorized, based on pressure gauges, they have the advantage of offering a continuous scale and no longer logarithmic values. With the Randall-Selitto analgesimeter [START_REF] Randall | A method for measurement of analgesic activity on inflamed tissue[END_REF]Kayser et al., 1990), the plantar surface of the rat's paw is placed on a fixed element and a mobile element exerts an increasing pressure on the other face. According to the protocols, the parameter measured will be either the threshold expressed in grams of appearance of a withdrawal reflex or that of a vocalization. This test gives highly stable and reproducible values, but requires a strong behavioural expertise [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. Indeed, the rat is restrained in a vertical non-natural position to maintain its paw on the apparatus. A similar system has been developed to assess mechanonociception in models of arthritis where calibrated forceps are oriented along the joint line and an increasing compression force is applied [START_REF] Ji | Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala[END_REF][START_REF] Amorim | Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis[END_REF].

The various tests that we described above have been used to validate the presence of nociceptive hypersensitivity in animal models of pain used to study the anxiodepressive comorbidity. Most of these studies were based on measuring the evoked nociceptive response instead of spontaneous or ongoing pain since the latter cannot be easily measured in rodents. In the past decade, however, an effort from some research groups has focused on the search for objective and quantitative measures of pain, or at least for indirect parameters that may reflect the ongoing pain in the animal [START_REF] Mogil | Animal models of pain: progress and challenges[END_REF][START_REF] Deuis | Methods Used to Evaluate Pain Behaviors in Rodents[END_REF]. One of the strategies to obtain such parameters has been based on the evaluation of the affective dimension of the pain experience, which comprises its unpleasantness and salient fear negative-stimuli-related escape and avoidance behaviours [START_REF] Price | Psychiatric co-morbidities in patients with chronic peripheral neuropathic pain: a multicentre cohort study[END_REF]Fuchs & McNabb, 2012;[START_REF] Navratilova | Evaluation of reward from pain relief[END_REF]. One of the most frequently used methods to evaluate such avoidance consists in giving the choice to the animal between environments associated or not with the painful experience. This can for example be done in response to mechanical stimulation [START_REF] Labuda | A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats[END_REF][START_REF] Llorca-Torralba | Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model[END_REF], by using plates with temperature gradient or allowing the choice between two surfaces with different temperatures [START_REF] Moqrich | Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin[END_REF]. Another indirect measure of ongoing pain has been done by using a modified version of the conditioned place preference test, which is based on an animal's preference for a context paired with a pain-relieving treatment [START_REF] King | Unmasking the tonic-aversive state in neuropathic pain[END_REF]Barthas et al.,

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This article is protected by copyright. All rights reserved 2015; [START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF], such as intrathecal or systemic administration of non-rewarding analgesic drug (Sufka, 1994;[START_REF] Navratilova | Evaluation of reward from pain relief[END_REF].

Another strategy is to consider the emotional component of pain through facial or vocal expression. The "grimace scale" of pain can actually be recognized and evaluated in rats (Sotocinal et al., 2011) and mice [START_REF] Langford | Coding of facial expressions of pain in the laboratory mouse[END_REF] exposed to acute or short-term pain.

Unfortunately, as observed in chronic pain patients, this facial signature may not necessarily be present in chronic pain models [START_REF] Langford | Coding of facial expressions of pain in the laboratory mouse[END_REF]. The evaluation of pain through ultrasonic vocalizations has also been explored by some teams [START_REF] Calvino | Ultrasonic vocalization (22-28 kHz) in a model of chronic pain, the arthritic rat: effects of analgesic drugs[END_REF][START_REF] Han | Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior[END_REF][START_REF] Kurejova | An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain[END_REF], but the reliability of this parameter still remains low, limited to certain pain models and not necessarily relevant in a context of chronic pain (Jourdan et al., 2002;[START_REF] Wallace | Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain[END_REF].

Evaluating anxiety-like and depression-like behaviours in animal models of chronic pain

Anxiety-like behaviours

Elevated plus maze

One of the most widely used test to assess anxiety-like behaviours in rodents is the elevated plus maze (EPM). It has been pharmacologically validated in rats [START_REF] Pellow | Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat[END_REF] and in mice [START_REF] Lister | The use of a plus-maze to measure anxiety in the mouse[END_REF] using chlordiazepoxide, diazepam, phenobarbitone and yohimbine. The EPM apparatus consists in a cross composed of two open and two closed arms, joined by a common central platform (Narita et al., 2006a). This apparatus is set 40 to 80 cm above the floor and the closed arms are enclosed by 15 to 40 cm walls depending on the considered species (Narita et al., 2006a;Hasnie et al., 2007b;Goncalves et al., 2008;[START_REF] Roeska | Anxiety-like behaviour in rats with mononeuropathy is reduced by the analgesic drugs morphine and gabapentin[END_REF]. Animals are placed in the middle of the apparatus and let free to explore the maze. The number of entries as well as time spent in both closed and open arms is assessed over 5 to 15 minutes depending on the protocols (Narita et al., 2006a;[START_REF] Ji | Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats[END_REF]. Arm entry and exit are often considered when all four paws are into or out of a given arm. This paradigm induces a conflict between the innate exploratory

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This article is protected by copyright. All rights reserved intensity used in their paradigm it is difficult to conclude about the optimal light setting. Besides, analysis of the number of arm entries can be used as an indicator of the animal locomotion, a decrease in the number of arm entries suggesting a deficit in locomotion. This internal control is then very useful to make sure that the effect seen in the EPM arises from anxiety-like behaviour and not from motor impairment [START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF].

Concerning pain induced-anxiety, the majority of published studies using the EPM test succeeded in highlighting the presence of anxiety-like behaviours in both mouse and rat pain models (Figure 2). Indeed, a decreased time spent in the open arms of the EPM has been observed after 5 to 14 post-induction days in fibromyalgia models (Green et al., 2011;Liu et al., 2014;[START_REF] Wu | 5-HT in the dorsal raphe nucleus is involved in the effects of 100-Hz electro-acupuncture on the pain-depression dyad in rats[END_REF][START_REF] Nazeri | Evidence of Altered Trigeminal Nociception in an Animal Model of Fibromyalgia[END_REF]) (see also Table 3) and within a few hours to one day (Fernandez-Guasti et al., 2005;[START_REF] Ji | Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala[END_REF]do Nascimento & Leite-Panissi, 2014) in inflammatory models (Table 2). The anxiety-like behaviours observed in the EPM for rodents with inflammatory pain have also been shown to last up to 3-4 weeks post-pain induction (Narita et al., 2006a;Narita et al., 2006b;[START_REF] Parent | Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain[END_REF][START_REF] Amorim | Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis[END_REF][START_REF] Borges | Reversal of monoarthritis-induced affective disorders by diclofenac in rats[END_REF]Wang et al., 2015b). In traumatic neuropathic pain models, a decrease in the time spent in the open arms has mainly been observed after 3 to 4 weeks post-surgery (Table 1, Figure 3) (Narita et al., 2006a;Narita et al., 2006b;[START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF][START_REF] Matsuzawa-Yanagida | Usefulness of Accepted Article This article is protected by copyright. All rights reserved antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites[END_REF][START_REF] Roeska | Effect of high trait anxiety on mechanical hypersensitivity in male rats[END_REF][START_REF] Leite-Almeida | Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior[END_REF][START_REF] Caspani | Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats[END_REF][START_REF] Li | Effects of chronic electroacupuncture on depression-and anxiety-like behaviors in rats with chronic neuropathic pain[END_REF][START_REF] Li | Effects of chronic electroacupuncture on depression-and anxiety-like behaviors in rats with chronic neuropathic pain[END_REF][START_REF] Sawada | Suppression of bone marrow-derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice[END_REF][START_REF] Ji | 5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors[END_REF][START_REF] Wang | Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain[END_REF]Ferreira-Chamorro et al., 2018;[START_REF] Chen | Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury[END_REF]. This phenotype is usually still present at 8 weeks post-surgery (Suzuki et al., 2007;[START_REF] Lyons | Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors[END_REF][START_REF] Descalzi | Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression[END_REF][START_REF] Sang | Plastic change of prefrontal cortex mediates anxiety-like behaviors associated with chronic pain in neuropathic rats[END_REF] or even at 19-24 post-operative weeks in the SNI model [START_REF] Seminowicz | MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain[END_REF], but it can also start to recover at this time point in PSNL (Gonzalez-Sepulveda et al., 2016). Some studies, however, failed to show the presence of anxiety-like behaviours, in some cases due to the time point chosen for the test. Indeed, anxiety-like behaviours related to peripheral neuropathic pain in this test tend to mostly develop around 3-4 weeks following induction of the chronic pain, so testing too early may sometimes explain the lack of anxiety-like behaviours in some studies [START_REF] Kontinen | Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy[END_REF]Hasnie et al., 2007b;[START_REF] Roeska | Anxiety-like behaviour in rats with mononeuropathy is reduced by the analgesic drugs morphine and gabapentin[END_REF]Gregoire et al., 2012;[START_REF] Pitzer | Inflammatory and neuropathic pain conditions do not primarily evoke anxiety-like behaviours in C57BL/6 mice[END_REF]. Conversely, anxiety-related behaviours generally disappear after a certain delay, thus testing this component of chronic pain at a very late time points can be misleading (Goncalves et al., 2008;[START_REF] Pitzer | Inflammatory and neuropathic pain conditions do not primarily evoke anxiety-like behaviours in C57BL/6 mice[END_REF]. Moreover, it has been shown that the side of the nerve lesion might also impact the affective consequences of chronic pain. For instance, Leite-Almeida et al. showed that when SNI is performed on the left nerve, male Wistar-

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This article is protected by copyright. All rights reserved Han rats displayed more pronounced anxiety-like profile than when SNI was performed on the right nerve [START_REF] Leite-Almeida | Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior[END_REF]. Finally, the repetition of the EPM procedure on the same animals can also effect the interpretation of results [START_REF] Hubbard | Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study[END_REF]. Indeed, the EPM has been depicted as sensitive to one-trial tolerance phenomenon, namely a decrease of time spent in open arms with the repetition of the test and independent of experimental groups (Tucker & McCabe, 2017).

Elevated zero maze

To avoid the one trial tolerance phenomenon, the elevated-zero maze (EZM) was developed and validated for anxiety assessment using diazepam and chlordiazepoxide treatments [START_REF] Shepherd | Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety[END_REF]. It consists of an elevated (40-70 cm above from floor) annular platform (5-10 cm wide; 46-120 cm diameter) with two opposite closed quadrants and two open quadrants (Urban et al., 2011;[START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF]. Animals are placed in one of the enclosed quadrants and let free to explore the apparatus. As for the EPM, the number of entries and time spent in open quadrants are usually recorded during 5 minutes [START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF][START_REF] Llorca-Torralba | Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model[END_REF][START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF]. Other parameters can also be considered like head dips or "stretch attend" postures if a finest assessment of anxiety-related behaviours is searched for [START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF][START_REF] Alba-Delgado | The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain[END_REF]. As for the EPM, the EZM produces a conflict between exploratory behaviour and fear induced by a bright (the light intensity is set between 40 and 100 lux) and open environment [START_REF] Kulkarni | Elevated zero maze: a paradigm to evaluate antianxiety effects of drugs[END_REF]. Thereby, a decrease in the time spent in open quadrants suggests the development of anxiety-like behaviours.

Using this test, studies showed that neuropathic pain conditions, either caused by traumatic event [START_REF] Alba-Delgado | Chronic pain leads to concomitant noradrenergic impairment and mood disorders[END_REF]Dimitrov et al., 2014;[START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF][START_REF] Alba-Delgado | The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain[END_REF][START_REF] Llorca-Torralba | Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model[END_REF] or by streptozotocin-induced diabetes [START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF], can decrease the time spent in open quadrants at 4 to 6 weeks post-surgery, indicating the development of chronic pain-induced anxiety-like behaviours (Table 1, Figure 3).

Interestingly, Martinez-Navarro and collaborators selected Swiss albino male mice based on their high or low anxiety trait at the beginning of the experiment, and demonstrated that animals expressing higher anxiety-like behaviours prior neuropathic pain induction developed anxiety-like behaviours at earlier time points (2 weeks) [START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF]. In CFA-induced inflammatory pain, anxiety-like behaviours were observed using the EZM one day after induction [START_REF] Refsgaard | Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state[END_REF], while these behaviours were observed at week 41 in an osteoarthritis

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This article is protected by copyright. All rights reserved model (Griffin et al., 2010) (Table 2). However, Urban and collaborators couldn't observe anxiety-like behaviours using the EZM in the SNI, CCI and CFA models (Urban et al., 2011). For the CFA model, the late time point used in this study, 33 days post-induction (against 1 to 10 days for other studies), could explain the lack of effect in EZM. Indeed, conversely to Urban and collaborators, other studies assessing anxiety-like behaviours (with either the EPM or the EZM) in CFA-induced inflammation never tested it after 4 post-induction weeks [START_REF] Chen | The contribution of TNFalpha in the amygdala to anxiety in mice with persistent inflammatory pain[END_REF]do Nascimento & Leite-Panissi, 2014;[START_REF] Refsgaard | Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state[END_REF]. Regarding the results obtained in the SNI and CCI models, the authors suggest that the absence of effect could arise from the protocol used in their study (Urban et al., 2011).

Open field

Anxiety-related behaviours can also be assessed with the open field test (OF). The OF consists in a square arena (40x40x30 cm: mice, 100x100x60 cm: rats), lighted with dim to bright light (4-580 lux) (Wallace et al., 2007b;Zhu et al., 2017). Animals are placed in the centre of the OF (Hasnie et al., 2007a) or facing one wall of the arena (Zhu et al., 2017) and let free to explore the test. The time spent as well as the number of entries in the centre of the arena (area located 10 cm (mice) or 40 cm (rats) to the walls) are measured during 5 to 15 minutes. Again, this paradigm creates a conflict between the innate exploratory behaviour and the fear generated by an open and bright area. Administration of anxiolytic drugs such as diazepam or chlordiazepoxide was shown to elicit an increase in time spent and entries in the center area [START_REF] Choleris | A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field[END_REF].

When conducted in an inflammatory pain model, a decrease in time spent in the centre of the OF is observed from one to 28 post-induction days [START_REF] Kim | Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression[END_REF][START_REF] Parent | Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain[END_REF][START_REF] Chen | The contribution of TNFalpha in the amygdala to anxiety in mice with persistent inflammatory pain[END_REF][START_REF] Amorim | Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis[END_REF]Gregoire et al., 2014;[START_REF] Zhang | Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model[END_REF][START_REF] Zhang | Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model[END_REF]Tian et al., 2017;[START_REF] Yue | Anxiolytic effect of CPEB1 knockdown on the amygdala of a mouse model of inflammatory pain[END_REF] (Table 2). Liu and collaborators tested anxiety-like behaviours in the acid-induced hyperalgesia model of fibromyalgia and observed an effect 13 days after induction (Liu et al., 2014) (Table 3). Regarding models of neuropathic pain, OF results are quite heterogeneous (Table 1, Figure 2). Indeed, over 39 published studies, 25 showed decreased time spent in the centre of the OF at time points mainly between 2 and 8 weeks after pain induction; while the other 14 studies failed to find any effect in this test (Figure 3). A main explanation for these discrepancies could again arise from the time point used to assess anxiety-related behaviours. Indeed, some studies [START_REF] Kontinen | Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy[END_REF][START_REF] Norman | Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury[END_REF][START_REF] Kodama | Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury[END_REF] only tested animals at early or very late stage of chronic pain (Goncalves et al., 2008)

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This article is protected by copyright. All rights reserved although it is known that the temporality of the development of affective consequences of chronic pain is a critical parameter [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF]. The choice of the neuropathic model has also an impact on results obtained in OF. For instance, in spinal cord injury models either no differences or cohort-dependent effect was observed (Galan-Arriero et al., 2014;[START_REF] Maldonado-Bouchard | Inflammation is increased with anxiety-and depression-like signs in a rat model of spinal cord injury[END_REF][START_REF] Boadas-Vaello | Graded photochemical spinal cord injury results in chronic hyperalgesia and depression-like behaviour but no anxiety exacerbation in female BALB/c mice[END_REF]. Also, in the PSNL model (Figure 1), near 50% of the studies didn't report change in OF (Hasnie et al., 2007a;Hasnie et al., 2007b;[START_REF] Kodama | Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury[END_REF]. The reason why huge variability is frequently observed with this test can also be due to the protocol parameters, such as light setting (from 4 to more than 100 lux), test duration (4 to 60 min), area size, definition of the central zone etc. Indeed, over the 18 studies for which light parameters are provided in methods, 10 out of the 14 studies conducted with a light intensity set at 60 lux or less succeeded in demonstrating pain-induced anxiety-like behaviours (Hasnie et al., 2007a;Suzuki et al., 2007;Wallace et al., 2007a;Wallace et al., 2007b;Wallace et al., 2007c;[START_REF] Avila-Martin | Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury[END_REF][START_REF] Avila-Martin | Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury[END_REF][START_REF] Missig | Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal-Regulated Kinase Signaling Regulates the Emotional Component of Pain[END_REF][START_REF] Zhang | Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain[END_REF]Gong et al., 2018), while the 4 studies using an intensity equal or higher than 100 lux failed [START_REF] Kontinen | Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy[END_REF][START_REF] Kodama | Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury[END_REF]Urban et al., 2011;[START_REF] Chen | Anxiety-and activity-related effects of paracetamol on healthy and neuropathic rats[END_REF]. These data suggest that too high light intensity might induce anxiety strong enough in controls to mask the difference between experimental groups, and that milder light setting should perhaps be preferred for better discrimination between groups. Finally, it has been shown that even when the test conditions are strictly controlled, a strong variability between different laboratories can still be present [START_REF] Robinson | Between and within laboratory reliability of mouse behaviour recorded in home-cage and open-field[END_REF].

Regarding these results, it seems that the OF should not be the only test used to assess anxiety in pain condition, and indeed several groups rather employ a battery of behavioural tests to depict rodent emotional state (Suzuki et al., 2007;[START_REF] Leite-Almeida | The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats[END_REF]Wang et al., 2015b;[START_REF] Descalzi | Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression[END_REF] and often use the OF as a marker of locomotor activity rather than an anxiety test (Goncalves et al., 2008;[START_REF] Lyons | Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors[END_REF][START_REF] Wu | Dorsal root ganglion transcriptome analysis following peripheral nerve injury in mice[END_REF][START_REF] Pan | Ketamine differentially restores diverse alterations of neuroligins in brain regions in a rat model of neuropathic paininduced depression[END_REF].

Light/dark box test

Another test aiming at assessing anxiety-like behaviour is the light/dark box test (LDB) developed by Crawley and Goodwin who also showed the sensitivity of this test to benzodiazepines [START_REF] Crawley | Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines[END_REF]. Several other groups reproduced the results obtained by Crawley and Goodwin with various benzodiazepines, as well as with drugs acting on the serotonergic neurotransmission system (for an extensive review see [START_REF] Bourin | The mouse light/dark box test[END_REF]). The LDB is formed by two communicating chambers, one dimly lit with black walls and one brightly lit (100-

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placed in the dark compartment and let free to explore the apparatus for 5-10 minutes. Entries and time spent in the light box are recorded, and latency to enter in the light box and rearing can also be considered among parameters [START_REF] Lyons | Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors[END_REF]. Since the bright compartment represents an aversive environment for rodents, a decrease in the time spent/or number of entries in this zone is defined as an anxiety-like behaviour.

As for the previously described tests, when LDB is performed in neuropathic pain models anxiety-like behaviours can be observed 4 (Narita et al., 2006a;Narita et al., 2006b;[START_REF] Matsuzawa-Yanagida | Usefulness of Accepted Article This article is protected by copyright. All rights reserved antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites[END_REF][START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF][START_REF] Chen | The contribution of TNFalpha in the amygdala to anxiety in mice with persistent inflammatory pain[END_REF][START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF]Guimaraes et al., 2019) to 8 weeks post-surgery (Suzuki et al., 2007;[START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF][START_REF] Lyons | Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors[END_REF][START_REF] Barthas | Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression[END_REF][START_REF] Lyons | Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury[END_REF][START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF], except for the SCI model in which no decrease in time spent in light box was detected [START_REF] Boadas-Vaello | Graded photochemical spinal cord injury results in chronic hyperalgesia and depression-like behaviour but no anxiety exacerbation in female BALB/c mice[END_REF] (Table 1, Figure 2 & 3). Three studies also demonstrated a decrease in the time spent in the light box already detectable at 2 weeks after neuropathic pain induction [START_REF] Mutso | Abnormalities in hippocampal functioning with persistent pain[END_REF]Gambeta et al., 2018;[START_REF] Chen | Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury[END_REF]. Again difficulties to show anxiety-like behaviours can generally be explained by the testing time point being too early [START_REF] Kontinen | Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy[END_REF][START_REF] Pitzer | Inflammatory and neuropathic pain conditions do not primarily evoke anxiety-like behaviours in C57BL/6 mice[END_REF] or too late [START_REF] Pitzer | Inflammatory and neuropathic pain conditions do not primarily evoke anxiety-like behaviours in C57BL/6 mice[END_REF]. When done in inflammatory condition, anxiety-like behaviour was observed in the LDB from 1 day to 28 days after induction (Narita et al., 2006a;Narita et al., 2006b;[START_REF] Parent | Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain[END_REF]do Nascimento & Leite-Panissi, 2014;[START_REF] Omorogbe | Jobelyn((R)) attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice[END_REF] (Table 2).

Social interaction

The social interaction test (SI) was first developed to enable a measure of anxiety based on ethological behaviours and to replace tests including electric shock or food deprivation used so far (File & Seth, 2003). This test was shown to be sensitive to anxiogenic (yohimbine, benzodiazepine receptor antagonists, picrotoxin) and anxiolytic drugs (lorazepam, diazepam, buspirone), as well as to stress-related hormones like the corticotropin-releasing factor and the adrenocorticotropic hormone (File & Seth, 2003). Originally, animals were isolated for several days prior to testing, but recent studies only used an isolation of 5 to 120 minutes (Gregoire et al., 2012;[START_REF] Hisaoka-Nakashima | High-mobility group box 1mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain[END_REF]. After this isolation period, a juvenile congener is introduced in the cage and the amount of time spent in interaction (sniffing, following, grooming, licking) is recorded during 5 min [START_REF] Hisaoka-Nakashima | High-mobility group box 1mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain[END_REF]. For a more global recording of rodent social spontaneous behaviours, Benbouzid and collaborators did a video monitoring in home cage during Accepted Article juvenile congener.

The number of studies using the SI as a measure of anxiety-like behaviours in pain conditions is quite limited. Yet, when conducted in neuropathic pain models, a decrease in SI has been observed at 4 [START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF]6 (Hisaoka-Nakashima et al., 2019) weeks postsurgery (Table 1, Figure 4). The studies conducted by [START_REF] Maldonado-Bouchard | Inflammation is increased with anxiety-and depression-like signs in a rat model of spinal cord injury[END_REF] or Gregoire (Gregoire et al., 2012) only tested animals before 3 weeks postsurgery, which might explain the absence of decrease in SI (Table 1, Figure 4). Indeed, the work conducted by Benbouzid and collaborators even report an increase in time dedicated to social contact at 2 post-operative weeks [START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF]. Regarding the sole study conducted in an inflammatory model (Gregoire et al., 2014), a decrease in SI was observed 2-3 weeks after CFA injection.

Marble burying test

Originally used to assess anxiety-like behaviours because of its sensitivity to anxiolytic drugs such as diazepam or buspirone [START_REF] Njung'e | Evaluation of marble-burying behavior as a model of anxiety[END_REF], the marble burying test (MB) is now thought to also be a potential test for the detection of compulsive behaviours (Thomas et al., 2009;[START_REF] Angoa-Perez | Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice[END_REF]. MB is performed in cages (same dimension as the home cages) containing 3-5 cm of fine sawdust. Twelve to 25 glass marbles (1 cm diameter) are evenly spaced on top of the sawdust. Animals are placed individually into the cages and left undisturbed for 15-30 min. After this period animals are removed, and buried marbles are counted. Marbles are considered buried if two thirds or more of their surface is covered by sawdust. The number of buried marbles is considered as a measure of animal anxiety and/or compulsive behaviour (Jimenez-Gomez et al., 2011).

When used in neuropathic pain models, the MB highlights compulsive/anxiety-like behaviours at time-points between 28 to 46 days post-surgery [START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF][START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF]Guida et al., 2015;[START_REF] Aguilar-Avila | beta-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice[END_REF] 4). In an inflammatory pain model induced by intraplantar CFA injection, the increase in buried marbles occurred within 5 weeks post CFA injection (Urban et al., 2011).

Hole-board test

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This article is protected by copyright. All rights reserved While the hole-board test (HB) can also give an insight into anxiety-like behaviours, it is less commonly used in the study of pain and mood disorder comorbidity. The HB device consists of a square plate (around 40x40 cm dimension) surrounded by walls and containing 9 [START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF] or 16 holes (Montserrat-de la [START_REF] Paz | Validation and additional support for an experimental animal model of fibromyalgia[END_REF], around 3 cm diameter each, equally spaced on 3 to 4 rows. Animals are placed in the periphery [START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF] or in the centre (Montserrat-de la [START_REF] Paz | Validation and additional support for an experimental animal model of fibromyalgia[END_REF] of the arena, and let free to explore the apparatus for 5 to 15 minutes (Montserrat-de la [START_REF] Paz | Validation and additional support for an experimental animal model of fibromyalgia[END_REF][START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF]. The number of nose-pokes, recorded by infrared photocells in the hole, is used as a measure of anxiety-like behavior since diazepam or chlordiazepoxide administration increase nosepoke numbers while anxiogenic compounds (FG7142, beta-CCM; inverse agonists of the benzodiazepine site of GABAa receptors) decrease it (Takeda et al., 1998). A decrease in the number of nose-pokes then reflects anxiogenic condition. Besides, the time spent in the centre of the HB is also recorded as a measure of anxiety (like in the OF), and the total distance travelled is an indicator of locomotor activity and thus serves as an internal control for motor function [START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF].

In a neuropathic pain model, a decrease in nose-poke activity has been observed at 4-6 postoperative weeks [START_REF] Sieberg | Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients[END_REF]. In a fibromyalgia model, this effect is already present at 3 post-induction days (Montserrat-de la [START_REF] Paz | Validation and additional support for an experimental animal model of fibromyalgia[END_REF].

Burrowing test

This test was first introduced by Deacon and collaborators in 2001, and relies on the natural burrowing behaviour of rodents [START_REF] Deacon | Burrowing into prion disease[END_REF][START_REF] Deacon | Assessing burrowing, nest construction, and hoarding in mice[END_REF]. The burrowing test (BT) was proposed as a measurement of laboratory animals well-being since burrowing deficit are among the first behaviours to be detectable when rodents undergo stressful condition (Jirkof, 2014). The testing takes place in new cages similar to animal's home cages. Hollow plastic tubes (32 cm long, 10 cm diameter for rats) sealed at one end and opened at the other end, are filled with gravel and disposed 6 cm above the ground to avoid loss of gravel [START_REF] Andrews | Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain[END_REF][START_REF] Huang | A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy[END_REF].

Test sessions are usually 2 hours long and latency to start burrowing and the amount of gravel displaced are recorded. In the BT, an increase in latency to burrow and a decreased amount of material displaced suggests the development of anxiety-like behaviours. Interestingly BT can be repeated on the same animals over time and thus gives the opportunity to conduct longitudinal studies. Note that several other protocols exist for burrowing assessment in rodent, and notably some using food pellet instead of gravel (for a review see (Jirkof, 2014)).

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This article is protected by copyright. All rights reserved In a model of inflammatory pain, burrowing behaviour deficits were seen at 10 postinduction days [START_REF] Andrews | Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain[END_REF]. Regarding neuropathic pain models, a decrease in burrowing has been observed at 10 post-operative days in SNL and PSNL [START_REF] Andrews | Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain[END_REF] and between 21 [START_REF] Huang | A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy[END_REF] and 77 days [START_REF] Andrews | Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain[END_REF] in TNT (Table 1, Figure 4). Notably, a standardization of the procedure and a comparison across laboratories have been recently done [START_REF] Muralidharan | Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain[END_REF][START_REF] Wodarski | Crosscentre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study[END_REF], making this test particularly interesting and reinforcing its validity for studying pain-related deficits.

Depression-like behaviours

Novelty-suppressed feeding test

The novelty-suppressed feeding (NSF) test can be used to assess both anxiety-and depressive-like behaviours, as demonstrated by its sensitivity to both anxiolytic (lorazepam, buspirone) and antidepressant drugs (imipramine, fluoxetine, amitriptyline) (Dulawa & Hen, 2005). The NSF consists in a 40x40x30 cm plastic box with the floor covered with 2 cm of sawdust. Animals are usually food-restricted for twenty-four hours prior to the test. At the time of testing, a single pellet of food is placed on a paper in the centre of the box. An animal is then placed facing a corner of the box and the latency to first contact and onset of eating the pellet is recorded within a 5 minutes period. This test induces a conflict between the drive to eat the pellet and the fear of venturing in the centre of the box. The increase in the latency to eat suggests anxiodepressive-like behaviours.

In each neuropathic pain model used so far, an increase in the latency to feed has been observed, mainly between 2 to 9 weeks post-surgery [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF][START_REF] Mutso | Abnormalities in hippocampal functioning with persistent pain[END_REF][START_REF] Barthas | The anterior cingulate cortex is a critical hub for pain-induced depression[END_REF][START_REF] Barthas | Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression[END_REF][START_REF] Wu | Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2Bmediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell[END_REF][START_REF] Poupon | Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin[END_REF][START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF][START_REF] Hisaoka-Nakashima | High-mobility group box 1mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain[END_REF]Jiang et al., 2019) (Table 1, Figure 5 &6). In a model of chemotherapy-induced neuropathy, Hache and collaborators showed an earlier onset of anxiodepressive-like behaviours compared to traumatic models (Hache et al., 2015) (Table 1, Figure 5 &6). In the biogenic amine depletion model of fibromyalgia, an increase in the latency to feed was seen 4 to 5 post-induction days [START_REF] Blasco-Serra | Depressive-like symptoms in a reserpine-induced model of fibromyalgia in rats[END_REF].

Forced swim test

A more common test to assess depressive-like behaviours in rodents is the forced swim test (FST), initially developed by Porsolt and collaborators in rats (Porsolt et al., 1977b) and mice (Porsolt et al., 1977a) in order to rapidly screen antidepressant drugs. Indeed, it was shown that immobility in

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This article is protected by copyright. All rights reserved the FST was decreased by tricyclic antidepressants, such as imipramine or amitriptyline (Porsolt et al., 1977b). From this initial validation and use as a simple drug-screening test, the FST has since been more widely used to also study depressive-like behaviours. In rats, a pre-test phase is required. Animals are gently lowered in an inescapable cylinder (height 50 cm, diameter 20 cm) containing 30 cm of water (23-25°C) for 15 minutes. The following day the rat is placed once again in the same apparatus and the duration of immobility phase is scored during 5 minutes [START_REF] Alba-Delgado | Chronic pain leads to concomitant noradrenergic impairment and mood disorders[END_REF]. For mice, there is no need to expose them to the pre-test, so animals are directly lowered into an inescapable cylinder (height 20-46 cm, diameter 10-25 cm) containing 14-20 cm of water (21-25°C) (Dimitrov et al., 2014;Gai et al., 2014;[START_REF] Descalzi | Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression[END_REF]Yang et al., 2019a). Here the test duration is 6 minutes, and since little immobility is generally observed during the first 2 minutes, the duration of immobility is quantified over the last 4 minutes of the 6 minutes test [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF]. The animals are considered immobile when they float in the water, in an upright position, and made only small movements to keep their head above water. In this paradigm, the impossibility to escape an aversive situation creates a despair state in the animals, reflected by immobility time, thus an increase in immobility time is considered as a depressive-like behaviour. Besides immobility time, differentiating active behaviours between climbing, defined as forepaw vigorous upward movements in and out of the water, and swimming can also be recorded [START_REF] Hu | Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW405833[END_REF][START_REF] Alba-Delgado | Chronic pain leads to concomitant noradrenergic impairment and mood disorders[END_REF]. This distinction will then allow a finest assessment of despair behaviour since it has been shown that climbing behaviour was increased by norepinephrine-targeting antidepressant drugs, while swimming was modified by serotonin-targeted antidepressant drugs [START_REF] Detke | Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth[END_REF].

For most of the studies using FST to assess neuropathic pain-induced depression, an increased immobility time was observed at 4 weeks [START_REF] Hu | Amitriptyline rather than lornoxicam ameliorates neuropathic pain-induced deficits in abilities of spatial learning and memory[END_REF]Gai et al., 2014;[START_REF] Bruning | m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model[END_REF]Wang et al., 2015b;[START_REF] Chung | Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats[END_REF][START_REF] Wang | Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain[END_REF][START_REF] Poupon | Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin[END_REF] and8 weeks (Suzuki et al., 2007;Goncalves et al., 2008;[START_REF] Descalzi | Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression[END_REF][START_REF] Boadas-Vaello | Graded photochemical spinal cord injury results in chronic hyperalgesia and depression-like behaviour but no anxiety exacerbation in female BALB/c mice[END_REF][START_REF] Hisaoka-Nakashima | High-mobility group box 1mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain[END_REF] post-surgery (Table 1, Figure 5 &6). Interestingly, in the SNI and CCI models a shift to an earlier development of depressive-like behaviours can be observed. Indeed, over the 15 studies reporting an increase in immobility time in CCI, 8 showed it at or even before 2 weeks post-surgery (Fukuhara et al., 2012;[START_REF] Li | Effects of chronic electroacupuncture on depression-and anxiety-like behaviors in rats with chronic neuropathic pain[END_REF]Garg et al., 2017;[START_REF] Li | Ginsenoside Rf relieves mechanical hypersensitivity, depressionlike behavior, and inflammatory reactions in chronic constriction injury rats[END_REF] (see also Table 1, Figure 5 &6). For the SNI, among the 17 studies presenting depressive-like behaviour, 11 observed the development of deficits in active behaviour in this test before 2 weeks post-surgery (Stratinaki et al., 2013;Zhou et al., 2015;[START_REF] Laumet | Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain[END_REF]Xu et

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This article is protected by copyright. All rights reserved al., 2017; [START_REF] Pan | Ketamine differentially restores diverse alterations of neuroligins in brain regions in a rat model of neuropathic paininduced depression[END_REF]Yang et al., 2019b) (see also Table 1, Figure 5 &6). This timing could however be related to the severity of the model(s), and the fact that pain related to paw might by itself also affect motor (swimming) capacity, thus interfering with FST. In the CCI model, fluctuation in the time-dependency of depressive-like behaviours could also be explained by the inter-individual variability in pain induction that may be present in this model. Similarly, in a chemotherapy-induced neuropathy an early onset of depressive-like behaviour has been reported [START_REF] Redivo | Effect of omega-3 polyunsaturated fatty acid treatment over mechanical allodynia and depressive-like behavior associated with experimental diabetes[END_REF]Toma et al., 2017). Regarding inflammatory pain models, increased immobility time in FST has been detected between 7 and 35 post-induction days in CFA injected animals (Urban et al., 2011;[START_REF] Kim | Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression[END_REF][START_REF] Maciel | Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice[END_REF][START_REF] Borges | Reversal of monoarthritis-induced affective disorders by diclofenac in rats[END_REF][START_REF] Le | AMPAkines have novel analgesic properties in rat models of persistent neuropathic and inflammatory pain[END_REF]Hamann et al., 2016;[START_REF] Zhang | Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model[END_REF] and at 4 post-induction weeks in kaolin/carrageenan injected animals [START_REF] Amorim | Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis[END_REF]. Finally, when conducted in an acid injection-induced model of fibromyalgia, a decrease in immobility time was observed after 19-20 post-operative days (Liu et al., 2014), after 10-14 days in an intermittent cold stress model [START_REF] Nasu | A single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress[END_REF], and within few days in biogenic amine depletion models [START_REF] Nagakura | Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia[END_REF][START_REF] Arora | Possible involvement of oxido-nitrosative stress induced neuroinflammatory cascade and monoaminergic pathway: underpinning the correlation between nociceptive and depressive behaviour in a rodent model[END_REF][START_REF] De Souza | The effects of Phalpha1beta, a spider toxin, calcium channel blocker, in a mouse fibromyalgia model[END_REF][START_REF] Klein | Effects of Dseries resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice[END_REF]Siemian et al., 2019).

Tail-suspension test

A variant of the FST, also developed for antidepressant drug screening (Steru et al., 1985) and based on behavioural despair, is the tail suspension test (TST) in mice. It is sensitive to desipramine and amitriptyline (Steru et al., 1985). In TST, mice are suspended by the tail from a bar, 50 cm above the floor using an adhesive tape (1-2 cm from the proximal tail tip) [START_REF] D'aniello | d-Aspartic acid ameliorates painful and neuropsychiatric changes and reduces beta-amyloid Abeta1-42 peptide in a long lasting model of neuropathic pain[END_REF][START_REF] Wu | Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2Bmediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell[END_REF]. The test duration is 6 minutes and the immobility is measured during the whole test. Mice are considered as immobile when they hung down motionless (Gai et al., 2014). An increase immobility time is thought to represent depressive-like behaviour.

As for the FST, when the TST is used in CCI or SNI an early development of depressivelike behaviour (around 1 to 2 weeks) is observed (Zhao et al., 2014a;Zhao et al., 2014b;[START_REF] Wu | Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2Bmediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell[END_REF]Yang et al., 2019a). Similar results were found when using a chemotherapy-induced neuropathic pain model (Hache et al., 2015). For other neuropathic pain models, increased in immobility time was observed between 4 weeks and 2 months (Gai et al., 2014;[START_REF] Wu | Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways[END_REF]Guida et al., 2015;Ferreira-Chamorro et al., 2018;[START_REF] Aguilar-Avila | beta-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice[END_REF][START_REF] Zhang | The gap junction inhibitor INI-0602 attenuates mechanical allodynia and depression-like behaviors induced by spared nerve injury in rats[END_REF] (Table 1, Figure 5 &6). For inflammatory pain models, depressive-like behaviours have been highlighted by the TST 7 to 14 days after CFA injection [START_REF] Kim | Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression[END_REF][START_REF] Maciel | Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice[END_REF]

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This article is protected by copyright. All rights reserved [START_REF] Omorogbe | Jobelyn((R)) attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice[END_REF] and at 41 weeks in an osteoarthritis model (Griffin et al., 2010). Finally, in a fibromyalgia model, an increase in immobility time was observed within 3 post-induction days [START_REF] Klein | Effects of Dseries resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice[END_REF].

Sucrose preference test

The sucrose or saccharine preference test (SPT) was first described by Katz in 1982(Katz, 1982), and pharmacologically validated five years later by Willner and collaborators using the tricyclic antidepressant desipramine [START_REF] Willner | Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant[END_REF]. The purpose of this test is to assess in animals the decrease ability to feel pleasure, also called anhedonia, often reported in patients suffering from depression. Animals are individually housed for the duration of the test and are free to choose between water and sweet solution. An index of sweet solution preference is then calculated as the ratio of the sweet solution intake over total liquid intake. A decrease in this index suggests depressive-like behaviour [START_REF] Dellarole | Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling[END_REF][START_REF] Xie | Alterations in the inflammatory cytokines and brain-derived neurotrophic factor contribute to depression-like phenotype after spared nerve injury: improvement by ketamine[END_REF]. Today, a multitude of protocols are used to assess anhedonia in rodents. The sweet solution is mainly obtained using sucrose at a concentration varying from 0.5% (Gambeta et al., 2018) to 20% (Liu et al., 2014), but concentrations of 1% or 2% are the most used [START_REF] Bura | Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain[END_REF]Wang et al., 2015b;[START_REF] Porta | Effects of pregabalin on the nociceptive, emotional and cognitive manifestations of neuropathic pain in mice[END_REF]Zhu et al., 2017;[START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF]. To avoid a potential bias due to sucrose caloric value, it can be replaced by saccharine; the concentrations used are then comprised between 0.25 and 0.3% [START_REF] Wu | Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways[END_REF][START_REF] Refsgaard | Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state[END_REF]. Usually, a period of habituation is required prior testing. During this period, from 2 h (Zong et al., 2018) to 10 days [START_REF] Wang | A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats[END_REF], the bottles of water and sweet solution are often interchanged to prevent any side preference. Before the test session, a water deprivation is sometimes done with a duration varying between 2 [START_REF] Bura | Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain[END_REF] to 24 hours (Yang et al., 2019a). Finally, when considering the test duration, it varies from 15 minutes (Liu et al., 2014;[START_REF] Ji | 5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors[END_REF] to 48 hours (Urban et al., 2011;[START_REF] Wu | Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways[END_REF], but test sessions of 24 hours were the most commonly used (La [START_REF] Porta | Effects of pregabalin on the nociceptive, emotional and cognitive manifestations of neuropathic pain in mice[END_REF][START_REF] Li | Role of the Lateral Habenula in Pain-Associated Depression[END_REF][START_REF] Xie | Alterations in the inflammatory cytokines and brain-derived neurotrophic factor contribute to depression-like phenotype after spared nerve injury: improvement by ketamine[END_REF]Gong et al., 2018;[START_REF] Pan | Ketamine differentially restores diverse alterations of neuroligins in brain regions in a rat model of neuropathic paininduced depression[END_REF][START_REF] Wu | Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2Bmediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell[END_REF][START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF]. Despite all these protocol variations, the majority of reported studies could asses a presence of anhedonia between one week (Goffer et al., 2013;[START_REF] Xu | Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors[END_REF]Zhu et al., 2017;[START_REF] Wu | Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2Bmediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell[END_REF]Fang et al., 2019b;[START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF] to 10-11 weeks [START_REF] Wu | Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways[END_REF]Fu et al., 2018;Thompson et al., 2018;Fang et al., 2019a) after neuropathic pain induction (see also Table 1). However, this time window depends on the considered model.

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This article is protected by copyright. All rights reserved Regarding the CCI model, anhedonia tends to arise at 4 post-surgery weeks [START_REF] Dellarole | Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling[END_REF][START_REF] Li | Role of the Lateral Habenula in Pain-Associated Depression[END_REF][START_REF] Wang | Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4[END_REF]. Thus the lack of such behavioural deficit in the Gregoire and collaborator study could result from the fact that the test was performed at an earlier time point (Gregoire et al., 2012). Furthermore, two studies conducted in the SNI model showed the presence of individual differences (in pro-inflammatory cytokines or in gut microbiota) between animals that are resilient or sensitive to chronic pain induced-depression [START_REF] Xie | Alterations in the inflammatory cytokines and brain-derived neurotrophic factor contribute to depression-like phenotype after spared nerve injury: improvement by ketamine[END_REF]Yang et al., 2019a). These inter-individual differences might explain that effect in the SPT is sometimes cohort-dependant. In inflammatory pain models, a decrease in sucrose consumption was observed at 2 days post-induction [START_REF] Refsgaard | Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state[END_REF]) and lasted at least for 4 weeks [START_REF] Amorim | Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis[END_REF]. Finally, in a fibromyalgia model, Liu and collaborators observed anhedonia-like behaviour at 19-20 post-induction days (Liu et al., 2014).

Nesting test

Nesting is an innate behaviour in rodents, which allows them to shelter from environment, maintain a certain heat and reproduce (Jirkof, 2014). As for the burrowing test described before, a deficit in nesting is an early sign of decreased well-being that can be rescued with chronic fluoxetine treatment (Farooq et al., 2018). In the study of Toma and collaborators, mice were individually housed with all the previous nesting material removed from the cage and placed in a dark room for an acclimation period of 30 minutes. Then, a compressed cotton nestlet was weighted and cut into 6 pieces placed on the top of the wire cage lid, evenly spaced. After 120 minutes the nestlet pieces remaining on the cage lid were weighted and a score given to the nest constructed. A score of 0 was given if no nest was formed, a score of 1 if the mice build a partial nest and a score of 2 if the nest was completely constructed. A poor nest score and a high amount of remaining nestlet on the cage lid are thought to indicate depressive-like behaviours. With this nesting protocol, no nesting deficit was found in a paclitaxel-induced neuropathic pain model (Toma et al., 2017).

If one wants to assess the nesting behaviour more precisely, other protocols have been used in mood disorder-related studies (see (Jirkof, 2014) for a review); the most common protocol being the one described by Deacon in 2003, with a score from 0 (no nest formed) to 4 (established nest). This protocol also takes into account the shape of the nest (flat or dome shaped), the position in the cage (in the centre or at a corner) and is performed overnight (Deacon, 2006a;[START_REF] Deacon | Assessing burrowing, nest construction, and hoarding in mice[END_REF]. When using the nest test to assess depressive-like behaviour it is essential to make sure that

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This article is protected by copyright. All rights reserved the chosen protocol fits with the strain and sex of the animals used in the study. Indeed, differences in nest quality have been reported between males and females and between mice strains (Gaskill et al., 2012) or even between sub-strains (Sluyter et al., 1999).

Splash Test

The splash test (ST) is based on grooming, which is an important aspect of rodent behaviour and is often altered in animal models of depression [START_REF] Santarelli | Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants[END_REF][START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF]. Animals are placed in a new cage with 1 cm of sawdust and a solution of 10% sucrose is sprayed on their back. The time spent for grooming as well as the grooming location (head or body) are measured for 5 minutes. A grooming deficit in this test is thought to be related to the loss of interest in performing self-oriented minor tasks, thus indicating the development of depressive-like behaviours. Moreover, the administration of antidepressant drugs, such as imipramine, desipramine, fluoxetine or maprotiline, rescued the grooming deficits in the unpredictable chronic mild stress mouse model of depression [START_REF] Yalcin | Mouse strain differences in the unpredictable chronic mild stress: a four-antidepressant survey[END_REF]. When studied in a neuropathic pain model, more particularly in the cuff model, grooming deficits were reported between 6 and 9 postoperative weeks [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF][START_REF] Barthas | The anterior cingulate cortex is a critical hub for pain-induced depression[END_REF][START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF] (Table 1, Figure 5 &6). Interestingly, Sellmeijer and collaborators studied the long term effect of neuropathic pain on affective behaviours and found that grooming deficits were still present at 14 post-operative weeks but no more at 16 weeks. In this study the extinction of depressive-like behaviours seemed to follow the recovery of ongoing pain.

Discussion

For this review, we found and analysed 144 articles related to the study of anxiodepressive-like disorders induced by chronic pain. The first articles on the topic were published shortly before the 2000s, but there has been a sharp increase in the number of scientific publications in the recent years, pointing out the growing interest in the comorbidity between pain and anxiety and depression. While most published studies demonstrated the possibility to model anxiodepressivelike consequences of chronic pain in animals (and potentially highlighted the essential role of time in the development of these symptoms), contradictory results can still be observed. Beside the time factor, these differences between studies may be due to the chosen animal models and tests, as well as to the protocols used to perform the tests. Rather than relying on a single parameter in animal models, it may thus be important to prefer strategies that would include behavioural

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This article is protected by copyright. All rights reserved profiling based on performing several tests evaluating anxiety and depression [START_REF] Yalcin | A time-dependent history of mood disorders in a murine model of neuropathic pain[END_REF][START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF]. In this respect, choosing the appropriate tests and control condition is one of the critical steps to assess the affective consequences of chronic pain. For example, most of the tests measuring anxiety and depression in rodent depend on motor activity of animals (exploration of a novel environment, swimming), which might be altered by pain models and lead to bias in interpreting the results. It is thus critical to take into consideration the limit of each test. For instance FST is one of the most common paradigm used to detect depressive-like behaviours, despite the fact that besides antidepressants most psychostimulants could also decrease the immobility time [START_REF] Bogdanova | Factors influencing behavior in the forced swim test[END_REF]. Similarly when using the NSF, nesting, burrowing and marble burying tests, it should be kept in mind that these tests can in fact reflect various behavioural alterations at the same time, such as anxiety-or depressive-like behaviours for NSF (Dulawa & Hen, 2005), as well as obsessive compulsive-and autism-like behaviours for marble burying (Deacon, 2006b;[START_REF] Angoa-Perez | Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice[END_REF]. Furthermore, the experimenter should be careful with the order of tests when using several tests on the same animals. Indeed, some tests are anxiogenic per se, like the FST or TST, and should preferably be performed at the end of the experiments to avoid risks of interactions with other tests. In addition, tests based on the fear generated by novelty can often only be done once (EPM, NSF, EZM). On the other hand, tests based on ethologically relevant rodent behaviours, such as grooming, nesting or burrowing assessment, are potentially less anxiogenic. These tests, together with social interaction and the sucrose preference test, have the advantage to be repeatable and thus useful for a longitudinal follow-up of the animals (Thomas et al., 2009;Kaidanovich-Beilin et al., 2011). For chronic pain studies, such longitudinal testing strategy allows evaluating emotional state before pain induction and at various time points afterwards, thus using the animal as its own control. However, the development of new devices, such as PhenoWorld, can reinforce the possibility of testing animals in their habitual environment in automatic fashion, with limited interaction with the experimenter and on long term periods [START_REF] Castelhano-Carlos | PhenoWorld: a new paradigm to screen rodent behavior[END_REF]. In addition, apparatuses combining multiple tests (EPM, LDB and OF) in one testing paradigm [START_REF] Ramos | Animal models of anxiety: do I need multiple tests[END_REF] can also be a good alternative.

In this issue, we aimed at describing anxiodepressive tests that are already used for studying the comorbidity of chronic pain and mood disorders, but it is worth to mention that other paradigms such as intracranial self-stimulation (ICSS), sexual behaviours, electroencephalography or

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This article is protected by copyright. All rights reserved circadian rhythm analysis [START_REF] Castagne | Behavioral Assessment of Antidepressant Activity in Rodents Methods of Behavior Analysis in Neuroscience[END_REF] can also be used to address motivation, anhedonia and sleep pattern which are frequently altered in chronic pain.

The diversity of tests has already enable notable breakthrough in the understanding of mood disorders and chronic pain comorbidity in animal models. However, in order to homogenize and increase the reproducibility of results, it is critical that the description of the parameters used for the testing is detailed in articles' methods. Indeed, important information such as handling and housing conditions or habituation to the testing room are often missing and thus prevent to conclude on the best practices to adopt. For example, as already mentioned previously light setting in tests like OF, EPM, or EZM are rarely specified although the use of a too bright light can induces anxiety-like behaviours even in control animals. Indeed, creating more relevant procedures and standardization of some of the most variable procedures (such as OF and SPT) among laboratories would be of great interest for the field. NIMH proposed a Research Domain Criteria system (RDoC) defining the good practices when evaluating psychopathologies in animal models that might be of great use for achieving this goal [START_REF] Anderzhanova | Animal models in psychiatric research: The RDoC system as a new framework for endophenotype-oriented translational neuroscience[END_REF]. Moreover, an effort is still needed in developing new methods to measure pain that are not based on nociceptive reflex response. Indeed, no study so far could show a correlation between the degree of nociceptive hypersensitivity and the anxiodepressive-like consequences. Thus, animals with or without anxiety-and/or depression-like phenotype can show similar mechanical or thermal withdrawal thresholds in animal models of pain (Gui et al., 2016;[START_REF] Xie | Alterations in the inflammatory cytokines and brain-derived neurotrophic factor contribute to depression-like phenotype after spared nerve injury: improvement by ketamine[END_REF]Yang et al., 2019a). Conversely, a recent study showed that rats that do not develop mechanical allodynia after SNI can still develop anxiodepressive-like behaviours similarly to painful rats (Guimaraes et al., 2019). There is thus no correlation in rodent models of chronic pain between the nociceptive response and the development of anxiodepressive disorders, which is similar to clinical reports (Dickens et al., 2002;[START_REF] Jensen | Anxiety and depressive symptoms in fibromyalgia are related to poor perception of health but not to pain sensitivity or cerebral processing of pain[END_REF]Keltner et al., 2012;[START_REF] Bagnato | Pain threshold and intensity in rheumatic patients: correlations with the Hamilton Depression Rating scale[END_REF].

The above results may apparently question the causality relation between pain and emotional/cognitive disturbances. However, a causal link between pain and anxiodepressive consequences should not necessarily imply direct correlation between the intensity of nociceptive and anxiodepressive symptoms. Some observations suggest a temporal dissociation and partly independent mechanisms between these aspects of chronic pain (Zhou et al., 2015;Gui et al., 2016;Guimaraes et al., 2019). As example, in a model of sciatic nerve compression, mechanical hypersensitivity is no longer present 2 to 3 months after the surgery, while anxiodepressive-like behaviours can persist after the recovery of hypersensivity (Dimitrov et al., 2014;[START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF]

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This article is protected by copyright. All rights reserved 2018). Interestingly, one of these studies showed that ongoing pain can also persist beyond the recovery of nociceptive hypersensitivity [START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF], suggesting that reflex responses might not always be the best marker of pain.

Another limitation in the field relates to the fact that most published data used trauma models of neuropathic pain. While the cause of neuropathic pain is peripheral in a large set of patients, recent studies on anxiodepressive consequences of pain showed the potential involvement of distinct mechanisms with different neuropathic pain aetiologies, i.e. diabetic vs. trauma [START_REF] Alba-Delgado | Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model[END_REF]. For mechanistic aspects, it will thus be necessary to study these comorbidities in the context of the considered aetiologies, and in particular distinguish neuropathy, inflammation and fibromyalgia; and within neuropathic pain also consider metabolic diseases or neurotoxicity beyond the mostly used lesion models. Indeed, only three preclinical articles so far focused on the anxiodepressive-like aspects in chemotherapy-induced murine models of neuropathic pain (Hache et al., 2015;Toma et al., 2017;[START_REF] Poupon | Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin[END_REF]. Similarly, models mimicking neuropathic pain following viral infection (HIV or varicella zoster virus) have been poorly studied in regard to anxiodepressive-like symptoms. The study of central neuropathic pain also requires improvements. Indeed, preclinical studies using spinal cord injury either failed in showing anxiodepressive phenotype or reported a lack of reproducibility, whereas the comorbidity is clinically well established [START_REF] Haythornthwaite | Psychological aspects of neuropathic pain[END_REF][START_REF] Attal | The specific disease burden of neuropathic pain: results of a French nationwide survey[END_REF][START_REF] Lim | Anxiety and Depression in Patients with Traumatic Spinal Cord Injury: A Nationwide Population-Based Cohort Study[END_REF]. Studies testing similar mechanistic hypotheses in models relying on different aetiologies would likely be important in the field in order to identify shared mechanistic features (which may illustrate core or converging mechanisms of anxiety or of depression) and distinct mechanistic features (which may be relevant to individualised medicine).

Despite their imperfections, animal models have proved to be useful in dissecting the mechanisms underlying the comorbidity between chronic pain and mood disorders. Thus, the involvement of several brain structures, such as the prefrontal cortex (PFC) including the anterior cingulate cortex, the hippocampus, the amygdala, the nucleus accumbens (NAc), the lateral habenula, the ventral tegmental area, or the locus coeruleus (LC) has been shown (Yalcin et al., 2014;Doan et al., 2015;[START_REF] Humo | The molecular neurobiology of chronic pain-induced depression[END_REF]. Not only morphological, structural and functional modifications have been observed in these brain structures, but the implication of several neurotransmitter systems was also identified. For example, there is an increase in glutamatergic transmission in PFC, NAc, LC and amygdala (Goffer et al., 2013;Gonzalez-Sepulveda et al., 2016;[START_REF] Llorca-Torralba | Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model[END_REF][START_REF] Martinez-Navarro | Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain[END_REF]

leading to hyperactivities in

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This article is protected by copyright. All rights reserved these brain structures. Besides the glutamatergic system, the implication of the endocannabinoid system (Hasnie et al., 2007a;Wallace et al., 2007c;Jiang et al., 2019), and of serotoninergic, noradrenergic and opioidergic transmissions have also been identified in structures such as the LC, the amygdala, the striatum or the anterior cingulate cortex (ACC) (Narita et al., 2006b;[START_REF] Ji | 5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors[END_REF][START_REF] Alba-Delgado | The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain[END_REF][START_REF] Sang | Plastic change of prefrontal cortex mediates anxiety-like behaviors associated with chronic pain in neuropathic rats[END_REF]Thompson et al., 2018).

Beyond these anatomical and neurotransmitter-related information, animal studies on neuropathic pain also reported an implication of inflammatory mechanisms such as microglia activation (Galan-Arriero et al., 2014;[START_REF] Sawada | Suppression of bone marrow-derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice[END_REF][START_REF] Wu | Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways[END_REF][START_REF] Avila-Martin | Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury[END_REF][START_REF] Xu | Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors[END_REF]Ferreira-Chamorro et al., 2018) and/or pro-inflammatory cytokine production [START_REF] Norman | Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury[END_REF][START_REF] Dellarole | Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling[END_REF]Gonzalez-Sepulveda et al., 2016) in mood disorders accompanying chronic pain. At intracellular level, changes in the mitogen-activated protein kinases (MAPK) and indoleamine 2, 3-dioxygenase 1 (IDO1) were also reported [START_REF] Sawada | Suppression of bone marrow-derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice[END_REF]Zhou et al., 2015;[START_REF] Barthas | Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression[END_REF]. Looking at the mechanisms down to epigenetic level, the animal models and tests also allowed showing the recruitment of histone deacetylases (HDAC) [START_REF] Descalzi | Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression[END_REF] and of dimethyl-3-transferase (DM3T) [START_REF] Wang | Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4[END_REF]. From anatomy to neural transmission and cellular, molecular and epigenetic changes, the animal models and tests thus provided major contributions to our understanding of the mechanisms linking pain and mood (for review: (Yalcin & Barrot, 2014;Yalcin et al., 2014;[START_REF] Leite-Almeida | Animal Models for the Study of Comorbid Pain and Psychiatric Disorders[END_REF][START_REF] Humo | The molecular neurobiology of chronic pain-induced depression[END_REF].

In conclusion, despite their drawbacks that are highlighted in this review, preclinical models so far allowed exploring the anxiodepressive-like consequences of chronic pain. However, translational studies combining animal models and human condition, as well as side by side comparison of different animal models, should help us further improving the existing tests and guide us in developing new approaches to model this comorbidity in animals. Moreover, not all the patients suffering from chronic pain develop mood disorders. To better understand the mechanisms underlying the comorbidity between pain and mood disorders, it would thus also be critical to develop studies on such resiliency/susceptibility in animal models. In parallel, an effort is still needed in developing other measurements than the behavioural testing, such as the neuroimaging or biochemical biomarkers, in order to better characterize the anxiodepressive consequences of chronic pain.

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This article is protected by copyright. All rights reserved

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This article is protected by copyright. All rights reserved Box1. Definition and assessment of sensory symptoms or signs in pain.

COFER, Collège français des enseignants en rhumatologie; IASP, international association for the study of pain; ICD, international classification of diseases.

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This article is protected by copyright. All rights reserved (6) Sciatic nerve cuffing (Cuff; [START_REF] Mosconi | Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations[END_REF][START_REF] Benbouzid | Sciatic nerve cuffing in mice: a model of sustained neuropathic pain[END_REF]; (7) Spared nerve injury (SNI; [START_REF] Decosterd | Spared nerve injury: an animal model of persistent peripheral neuropathic pain[END_REF]; (8) Spinal cord injury (SCI; [START_REF] Behrmann | Spinal cord injury produced by consistent mechanical displacement of the cord in rats: behavioral and histologic analysis[END_REF]. The level of insertion of the nerve roots and therefore the associated dorsal root ganglia may vary according to the animals' strain hence the double level numbering on the dorsal root ganglia. "n" displayed in the figure corresponds to the number of publications relative to the test (see Table 1 for more details and references). EPM, elevated-plus maze; EZM, elevated zero maze. "n" displayed in the figure corresponds to the number of publications relative to the test (see Table 1 for more details and references). EPM, elevated-plus maze; EZM, elevated zero maze; LD, light-dark test; OF, open field. "n" displayed in the figure corresponds to the number of publications relative to the test (see Table 1 for more details and references). SI, social interaction. "n" displayed in the figure corresponds to the number of publications relative to the test (see Table 1 for more details and references). FST, forced swimming test; HST, horizontal suspension test; NSF, noveltysuppressed feeding; TST, tail suspension test. "n" displayed in the figure corresponds to the number of publications relative to the test (see Table 1 for more details and references). FST, forced swimming test; NSF, novelty-suppressed feeding; TST, tail suspension test.

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  behavior of the rodent and the fear generated by the open and heighten environment. Thus, a decrease in the amount of time spent in open arms is thought to reflect anxiety-like behaviour. To strengthen the aversion created by the open arms, it is possible to create a contrast in light setting between open and close arms. Thus, light intensity in closed arms may sometimes be below 10 lux while it can go up to 100 lux for the open arms. However, since very few studies indicate the light

Figure

  Figure 5 & 6 andTable 1). However, this time window depends on the considered model.

  and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. (IASP) Allodynia Pain due to a stimulus that does not normally provoke pain. (IASP) Analgesia Absence of pain in response to stimulation which would normally be painful. (IASP) Arthritis An informal way of referring to joint pain or joint disease. (COFER) Dysesthesia An unpleasant abnormal sensation, whether spontaneous or evoked. (IASP) Fibromylagia Syndrome characterized by chronic widespread pain at multiple tender points, joint stiffness, and systemic symptoms (e.g. mood disorders, fatigue, cognitive dysfunction and insomnia) without a well-defined underlying organic disease. (ICD) Hyperalgesia Increased pain from a stimulus that normally provokes pain. (IASP) Hyperpathia A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. (IASP) Hypoalgesia Diminished pain in response to a normally painful stimulus. (IASP) Inflammatory pain Inflammatory nociceptive pain is associated with tissue damage and the resulting inflammatory process. (COFER) Monoarthritis Inflammation of one joint (arthritis) at a time (ICD) Neuropathic pain Pain caused by a lesion or disease of the somatosensory nervous system. (IASP) Nociception The neural process of encoding noxious stimuli. (IASP) Nociceptive pain Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors. (IASP) Nociceptive stimulus An actually or potentially tissue-damaging event transduced and encoded by nociceptors. (IASP) Nociceptor A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli. (IASP) Osteoarthritis Group of distinct, but overlapping diseases, which may have different etiologies, but similar biological, morphological, and clinical outcomes affecting the articular cartilage, subchondral bone, ligaments, joint capsule, synovial membrane and periarticular muscles. (ICD)Accepted ArticleThis article is protected by copyright. All rights reservedPain thresholdThe minimum intensity of a stimulus that is perceived as painful. (IASP)ParaesthesiaAn abnormal sensation, whether spontaneous or evoked. (IASP)Rheumatoid arthritisPersistent and/or erosive disease that is defined as the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints, serologic abnormality, elevated acute-phase response, and symptom duration.(ICD)SensitizationIncreased responsiveness of nociceptive neurons to their normal input, and/or recruitment of a response to normally subthreshold inputs. (IASP)

Figure 1 .

 1 Figure 1. Experimental traumatic models of neuropathic pain. (1) Partial sciatic nerve ligation (PSNL; Seltzer et al., 1990); (2) Sciatic nerve ligation (SNL; Kim and Chung, 1992); (3) L5 spinal nerve ligation (variant of the SNL model; LaBuda and Little, 2005); (4) Tibial nerve transection (TNT; Lee and al., 2000); (5) Chronic constriction injury (CCI; Bennett and Xie, 1988);

Figure 2 .

 2 Figure 2. Anxiety-like behaviours in animal models of neuropathic pain.

Figure 3 .

 3 Figure 3. The impact of time on the anxiety-like behaviour in animal models of neuropathic pain.

Figure 4 .

 4 Figure 4. The impact of time on well-being in animal models of neuropathic pain.

Figure 5 .

 5 Figure 5. Depressive-like behaviours in animal models of neuropathic pain.

Figure 6 .

 6 Figure 6. The impact of time on depressive-like behaviour in animal models of neuropathic pain.

  Figure 1. 3

  Figure 3.

  Figure 4.

  Figure 6. TST 7 20 21 28 23 35 42 8 62 70 365 15 25 30 34 41 46 days post-surgery 1

  . In the late 1980s, Hargreaves et al. have described a test to differentiate the nociceptive response of the two hind paws in rodents: the Hargreaves test or Plantar® test

Table 1 ,

 1 (Figure 4). According to D'Aniello and collaborators, the changes seen in burying behaviours, at least in the SNI model, can last up to 1 year[START_REF] D'aniello | d-Aspartic acid ameliorates painful and neuropsychiatric changes and reduces beta-amyloid Abeta1-42 peptide in a long lasting model of neuropathic pain[END_REF] (Table 1, Figure

Table 1 .

 1 Summary of studies on the affective consequences of neuropathic pain.

	Pain model PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL PSNL SNL SNL SNL SNL Accepted Article	Species Mouse Rat Mouse Rat Mouse Rat Mouse Rat Mouse Mouse Mouse Rat Mouse Mouse Mouse Mouse Mouse Mouse Mouse Rat Mouse Rat Rat	Behavioural Test EPM; LD ALB at PO day 28 Results OF No ALB at PO day 14 EPM;OF; TST No ALB at PO days 7, 14, 28 No DLB at PO days 8, 15, 29 OF ALB at PO day 14 EPM; LD ALB at PO day 27 EPM No ALB at PO week 4 OF No ALB at PO day 10 BT Burrowing behaviour deficits at PO day 14 SPT DLB at PO day 16 EPM ALB at PO day 28 FST; TST DLB at PO week 4 EPM; OF; FST; SPT ALB at PO day 28; No DLB at PO day 28 FST DLB at PO week 4 EPM TST; MB ALB at PO days 5 to 47; DLB at post-surgery days 20 to 62 EPM; FST; SPT ALB at PO weeks 1, 3; DLB at PO week 3 EPM; OF FST ALB and DLB at PO day 30 EPM SPT ALB at PO day 15; DLB at PO day 10 SI FST; NSF ALB at PO week 6; DLB at PO week 8 FST; ST DLB at PO day 28 EPM; OF; LD No ALB at PO day 14 EPM; OF; LD; FST ALB at PO days 30, 56; DLB at PO days 15, 30, 56 OF ALB at PO day 14 FST DLB at PO day 29	References (Narita et al., 2006a; Narita et al., 2006b) (Hasnie et al., 2007a) (Hasnie et al., 2007b) (Wallace et al., 2007c) (Matsuzawa-Yanagida et al., 2008) (Roeska et al., 2008) (Kodama et al., 2011) (Andrews et al., 2012) (Bura et al., 2013) (Sawada et al., 2014) (Gai et al., 2014) (Wang et al., 2015b) (Bruning et al., 2015) (Gonzalez-Sepulveda et al., 2016) (La Porta et al., 2016) (Wang et al., 2017) (Martinez-Navarro et al., 2019) (Hisaoka-Nakashima et al., 2019) (Birmann et al., 2019) (Kontinen et al., 1999) (Suzuki et al., 2007) (Hasnie et al., 2007a) (Hu et al., 2010)

  ALB, anxiety-like behaviour; BT, burrowing test; CCI, chronic constriction injury; CION, infraorbital nerve constriction; DLB, depression-like behaviour; EPM, elevated-plus maze; EZM, elevated zero maze; FST, forced swimming test; gp120, immunodeficiency virus type 1 envelope glycoprotein 120; HB, hole-board test; HST, horizontal suspension test; LD, light-dark test, MB, marble burying test; NSF, novelty-suppressed feeding; OF, open field; PI, post-induction; PO, post-operative; PSNL, partial sciatic nerve ligation; SCI,

	spinal cord injury; SI, social interaction; SNI, spared nerve injury; SNL, sciatic nerve ligation; SPT, sucrose or saccharin preference test; ST, splash test; TIC, trigeminal inflammatory compression; TNT, tibial nerve transection; TST, tail suspension test; VZV, varicella zoster virus. Accepted Article Pain model Species Behavioural Test Results References CFA Mouse EPM; LD ALB at PI day 28 (Narita et al., 2006a; Narita et al., 2006b) CFA Mouse OF; EZM; MB; SI; FST; SPT No ALB and DLB at PI days 7-35 (Urban et al., 2011) CFA Rat OF; FST; TST; SPT ALB at PI days 7, 14; DLB at PI day 14 (Kim et al., 2012) CFA Rat EPM; OF; LD; SPT ALB at PI day 28 (Parent et al., 2012) CFA Rat BT Burrowing behaviour at PI day 10 (Andrews et al., 2012) CFA Mouse EPM; OF ALB at PI days 3, 7 (Chen et al., 2013) CFA Mouse FST; TST DLB at PI days 7-21 (Maciel et al., 2013) CFA Rat EPM; LD ALB at PI days 1, 3, 10 (do Nascimento & Leite-Panissi, 2014) CFA Rat EPM; FST ALB and DLB at PI day 28 (Borges et al., 2014) CFA Rat OF; SI; SPT ALB and DLB at PI weeks 2-3 (Gregoire et al., 2014) CFA Rat FST DLB at PI day 7 (Le et al., 2014) CFA Mouse EPM ALB at PI day 21 (Wang et al., 2015a) CFA Rat FST DLB at PI day 7 (Hamann et al., 2016) CFA Rat FST; SPT DLB at PI days 7-14 (Zhang et al., 2016) CFA Mouse EPM; OF ALB at day 21 (Guo et al., 2016) CFA Mouse EZM; SPT ALB at PI day 1; DLB at PI day 2 (Refsgaard et al., 2016) CFA Mouse EPM; OF ALB at PI day 21 (Sun et al., 2016) CFA Rat BT Burrowing behaviour at PI days 2-10 (Muralidharan et al., 2016) CFA Mouse EPM; OF ALB at PI week 2 (Tian et al., 2017) CFA Mouse LD; TST ALB and DLB at PI day 14 (Omorogbe et al., 2018) CFA Mouse EPM; OF ALB at PI week 1 (Yue et al., 2018) CFA Mouse EPM; OF; LD; FST No ALB and DLB at PI days 1-22 (Pitzer et al., 2019) CFA Mouse OF; EPM; TST; SPT ALB and DLB at PO week 3 (Zhou et al., 2019) K/C Rat EPM ALB at PI hours 5-6 (Ji et al., 2007) K/C Rat EPM; OF; FST; SPT ALB and DLB at PI week 4 (Amorim et al., 2014) Uric acid Rat (Fernandez-Guasti et EPM; MB ALB at PI hour 3 al., 2005) Accepted Article Osteoarthritis Mouse EZM; TST ALB and DLB at PI week 41 (Griffin et al., 2010)

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Table 2 .

 2 Summary of studies on the affective consequences of inflammatory pain.

	ALB, anxiety-like behaviour; BT, burrowing test; CFA, complete Freund's adjuvant; DLB, depression-like
	behaviour; EPM, elevated-plus maze; EZM, elevated zero maze; FST, forced swimming test; HB, hole-board
	test; K/C, kaolin/carrageenan; LD, light-dark test; MB, marble burying test; NSF, novelty-suppressed
	feeding; OF, open field; PI, post-induction; SI, social interaction; SPT, sucrose or saccharin preference test;
	ST, splash test; TST, tail suspension test.

Table 3 .

 3 Summary of studies on the affective consequences of fibromyalgia.

ALB, anxiety-like behaviour; BAD, biogenic amine depletion; DLB, depression-like behaviour; EPM, elevated-plus maze; FST, forced swimming test; HB, hole-board test; ICS, intermittent cold stress; NSF, novelty-suppressed feeding; OF, open field; PI, post-induction day; RCS, repeated cold stress; SPT, sucrose preference test; SSS, subchronic swim stress; TST, tail suspension test; USS, unpredictable sound stress.

This work was supported by the "Centre National de la Recherche Scientifique" (contract UPR3212), the University of Strasbourg, the "Agence Nationale de la Recherche" (Euridol ANR-17-EURE-0022), and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (24736).

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This article is protected by copyright. All rights reserved Dickens, C., Jayson, M. & Creed, F. (2002) Psychological correlates of pain behavior in patients with chronic low back pain. Psychosomatics, 43, 42-48. Dimitrov, E.L., Tsuda, M.C., Cameron, H.A. & Usdin, T.B. (2014) Anxiety-and depression-like behavior and impaired neurogenesis evoked by peripheral neuropathy persist following resolution of prolonged tactile hypersensitivity. J Neurosci, 34, 12304-12312. do Nascimento, G.C. & Leite-Panissi, C.R. (2014) Time-dependent analysis of nociception and anxiety-like behavior in rats submitted to persistent inflammation of the temporomandibular joint. Physiology & behavior, 125, 1-7. Doan, L., Manders, T. & Wang, J. (2015) Neuroplasticity underlying the comorbidity of pain and depression. Neural Plast, 2015, 504691. Dulawa, S.C. & Hen, R. (2005) Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neuroscience and biobehavioral reviews, 29, 771-783.

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This article is protected by copyright. All rights reserved Galan-Arriero, I., Avila-Martin, G., Ferrer-Donato, A., Gomez-Soriano, J., Piazza, S. & Taylor, J. ( 2015)

Early treatment with UR13870, a novel inhibitor of p38alpha mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain.

Neurosci Lett, 604, 69-74.

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This article is protected by copyright. All rights reserved Hamann, F.R., Zago, A.M., Rossato, M.F., Beck, V.R., Mello, C.F., de Brum, T.F., de Carvalho, L.M.,

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This article is protected by copyright. All rights reserved Atkinson, J.H., Grant, I. & Group, C. (2012) Health-related quality of life 'well-being' in HIV distal

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This article is protected by copyright. All rights reserved Siemian, J.N., Shang, L., Seaman, R.W., Jr., Zhu, Q., Zhang, Y. & Li, J.X. (2019) Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats.

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