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The International Association for the Study of Pain defines neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" (Treede et al., 2008). The associated changes can be observed in the peripheral as well as the central nervous system. The available literature discusses a wide variety of causes as predisposing for the development and amplification of neuropathic pain. Further, key interactions within sensory pathways have been discovered, but no common molecular mechanism leading to neuropathic pain has been identified until now. In the first part of this review, the pain mediating lateral spinothalamic tract is described. Different in vivo models are presented that allow studying trauma-, chemotherapy-, virus-, and diabetes-induced neuropathic pain in rodents. We furthermore discuss approaches to assess neuropathic pain in these models. Second, the current knowledge about cellular and molecular mechanisms suggested to underlie the development of neuropathic pain is presented and discussed. A summary of established therapies that are already applied in the clinic and novel, promising approaches closes the paper. In conclusion, the established animal models are able to emulate the diversity of neuropathic pain observed in the clinics. However, the assessment of neuropathic pain in the presented in vivo models should be improved. The determination of common molecular markers with suitable in vitro models would simplify the assessment of neuropathic pain in vivo. This would furthermore provide insights into common molecular mechanisms of the disease and establish a basis to search for satisfying therapeutic approaches.

International audience; 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 preclinical tools (models and tests) used for studying behavioural aspects of the comorbid relationship between chronic pain and anxiety and/or major depressive disorder. 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 allow 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.

The transcription factor deltaFosB is induced in the nucleus accumbens and dorsal striatum by chronic exposure to several drugs of abuse, and increasing evidence supports the possibility that this induction is involved in the addiction process. However, to date there has been no report of deltaFosB induction by drugs of abuse in the ventral tegmental area (VTA), which is also a critical brain reward region. In the present study, we used immunohistochemistry to demonstrate that chronic forced administration of cocaine induces deltaFosB in the rat VTA. This induction occurs selectively in a gamma-aminobutyric acid (GABA) cell population within the posterior tail of the VTA. A similar effect is seen after chronic cocaine self-administration. Induction of deltaFosB in the VTA occurs after psychostimulant treatment only: it is seen with both chronic cocaine and amphetamine, but not with chronic opiates or stress. The expression of deltaFosB appears to be mediated by dopamine systems, as repeated administration of a dopamine uptake inhibitor induced deltaFosB in the VTA, while administration of serotonin or norepinephrine uptake inhibitors failed to produce this effect. Time course analysis showed that, following 14 days of cocaine administration, deltaFosB persists in the VTA for almost 2 weeks after cocaine withdrawal. This accumulation and persistence may account for some of the long-lasting changes in the brain associated with chronic drug use. These results provide the first evidence of deltaFosB induction in a discrete population of GABA cells in the VTA, which may regulate the functioning of the brain's reward mechanisms.

Glucocorticoid hormones exert strong influences on central neurotransmitter systems. In the present work, we examined the functional consequences of corticosterone suppression on the dopaminergic transmission in the dorsolateral striatum by studying the expression of Fos-like proteins and extracellular dopamine levels. Glucocorticoid hormones were suppressed by adrenalectomy, and the specificity of the effects assessed by restoring physiological plasmatic corticosterone concentrations. We show that, in the dorsolateral striatum, glucocorticoids modify postsynaptic dopaminergic transmission. Suppression of glucocorticoids decreased the induction of Fos proteins in response to a direct agonist of dopamine D1 receptors (SKF 82958, 1.5 mg/kg, i.p.), but not the release of dopamine induced by morphine (2 mg/kg, s.c.) or the density of the limiting enzyme of dopamine synthesis, tyrosine hydroxylase. In contrast to the dopaminergic response to morphine, the response to cocaine (15 mg/kg, i.p.) was modified by the suppression of corticosterone. In this case, adrenalectomy increased cocaine-induced changes in extracellular dopamine but did not modify the expression of Fos-like proteins. This absence of changes in cocaine-induced Fos-like proteins might result from a compensatory mechanism between the increase in the dopaminergic response and the decrease in the functional activity of dopamine D1 receptors. The increased dopaminergic response to cocaine also contrasts with the decreased response previously observed in the shell of the nucleus accumbens [Barrot et al. (2000) Eur. J. Neurosci., 12, 973–979]. The present data highlight the profound heterogeneous influence of glucocorticoids within dopaminergic projections.

The calcium-binding protein calbindin-D28K is an anatomical marker that has been associated with resistance to neurodegeneration and with the electrophysiological characteristics of neurons. In this study, we compared the presence of calbindin in dopamine neurons projecting to three distinct functional regions of the striatal complex: the striatum, and the core and the shell of the nucleus accumbens. After iontophoretic injections of Fluoro-Gold in the dopaminergic terminal fields, the presence of tyrosine hydroxylase and calbindin were immunohistochemically assessed in the mesencephalon. It was found that the proportion of cells expressing calbindin was highest in the dopamine cells projecting to the core (72%), intermediate in the cells projecting to the shell (51%) and lowest in the cells projecting to the dorsolateral striatum (2.6%). These results do not support the idea that calbindin is a sufficient condition to confer resistance to neurodegeneration because shell-projecting neurons seem the most resistant to it. The present data also raise the question of the role of calbindin in the differences in firing characteristics among dopamine neurons projecting to the striatal complex.

Imidazoline binding sites are present in the striatal complex and in the extended amygdala and have been implicated in mood disorders. In this report we analysed the influence of these sites on the functional activity of the mesolimbic dopaminergic transmission, one of the major brain systems involved in the regulation of motivation and reward. We studied the effects of two imidazoline ligands, S23229 and S23230 (respectively S(+) and R(-) enantiomers of the S22687 or (5-[2-methyl phenoxy methyl] 1,3-oxazolin-2-yl) amine), on extracellular dopamine in the nucleus accumbens using microdialysis in freely moving rats. We compared these imidazoline ligands to cocaine, a dopamine uptake blocker known to increase extracellular dopamine concentrations. S23229 dose-dependently increased extracellular dopamine and locomotor activity. S23230 dose-dependently increased extracellular dopamine and produced a near-significant dose-effect on locomotor activity. S23229 had a stronger efficacy than S23230 and increased dopamine levels in the nucleus accumbens at an extent similar to the one of cocaine. These results suggest that central imidazoline binding sites could contribute to the functional regulation of the mesolimbic dopaminergic system.

The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos-like proteins selectively in the shell in response to cocaine. However, the induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain.

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Clinical studies in humans have associated some of these hormones with a generic sensation of 'well-being' and with pathologies such as depression. In rodents, the neurosteroid pregnenolone sulphate (Preg-S) has been shown to present antidepressant-like effects. These observations suggest that neurosteroids could interact with reward-related processes, mood and motivation. However, the possible neural substrates of such an effect remain unclear. In this report, we studied the action of Preg-S on the activity of the mesencephalic dopaminergic projection to the nucleus accumbens which is considered one of the biological substrates of motivation and reward. Both the direct effect of Preg-S and the influence of this hormone on the dopaminergic response to the pharmacological reward provided by the opiate morphine, were studied by means of microdialysis. Pregnenolone sulphate dose-dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg-S doses of 100, 200, and 400 pmol injected intracerebroventricularly. The stimulant effect of Preg-S on dopamine could mediate some of the behavioural effects of neurosteroids and in particular the interaction of these hormones with mood and motivation.

The dorsolateral striatum, and the core and shell of the nucleus accumbens are three major anatomical regions of the striatal complex. The shell is considered as a part of the extended amygdala, and is involved in the control of motivation and reward. The core and the striatum are considered central to sensory motor integration. In this study we compared the responses of these three regions to mild stress and drugs of abuse by measuring extracellular dopamine (DA) concentrations and Fos-like immunoreactivity (Fos-LI). The results are summarrized as follows. (i) In unchallenged conditions, extracellular DA concentrations were highest in the dorsolateral striatum and lowest in the core, whereas Fos-LI was highest in the shell and lowest in the dorsolateral striatum. (ii) After challenges that increase DA by depolarizing DAergic neurons (injection stress or 2 mg/kg morphine), the shell presented the largest increase in DA levels and Fos-LI. (iii) After the administration of a DA-uptake blocker (15 mg/kg cocaine), the percentage increase in DA was still largest in the shell. However, the absolute increase in DA and Fos-LI in the shell and the dorsolateral striatum were similar. (iv) After a full D1 agonist (SKF82958), Fos-LI was highest in the shell and lowest in the dorsolateral striatum. In conclusion, the nucleus accumbens shell seems to be the area of the striatal complex most functionally reactive to stress and drugs of abuse. However, the dorsolateral striatum and the core appear functionally distinct, as for most of the parameters studied these two regions differed.