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OBJECTIVE: Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs. METHODS: We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of beta(2)-AR was evaluated by studying beta(2)-AR(-/-) mice. We used von Frey filaments to assess mechanical allodynia. RESULTS: The antiallodynic action of nortriptyline was not affected by cotreatment with the alpha(2)-AR antagonist yohimbine, the beta(1)-AR antagonists atenolol or metoprolol, or the beta(3)-AR antagonist SR 59230A. On the contrary, the beta-AR antagonists propranolol or sotalol, the beta(1)/beta(2)-AR antagonists alprenolol or pindolol, or the specific beta(2)-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in beta(2)-AR-deficient mice. INTERPRETATION: Stimulation of beta(2)-AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between beta-blockers that affect beta(2)-AR and antidepressant drugs in patients treated for neuropathic pain. Ann Neurol 2009;65:218-225. [ABSTRACT FROM AUTHOR]

Large-scale field experiments on the Mediterranean corn borer, Sesamia nonagrioides Lefèbvre (Lepidoptera: Noctuidae), were carried out in 2004–2006 on maize [ Zea mays L. (Poaceae)] fields using ( Z)-11-hexadecenyl trifluoromethyl ketone, an antagonist analog of the pheromone of this species, to evaluate a possible reduction of damage caused by this pest. The effect of the treatments on the European corn borer, Ostrinia nubilalis Hübner (Lepidoptera: Crambidae), a sympatric species, was also determined. Evaluation of the success of the experiments was assessed by counting (i) the number of males caught by pheromone traps in treated and untreated fields, (ii) the number of plants attacked by both insects in both plots, and (iii) the number of larvae present in infested plants in both fields. Effectiveness of the treatment was high for the second generation of the Mediterranean corn borer, the most harmful to the crop (86–90% reduction in the number of plants attacked and 67–98% reduction in the number of larvae per plant in treated fields in comparison to untreated fields), and moderate for the third generation (reduction of 41–71% and 33–77%, respectively). Treatments were also effective for the second generation of the European corn borer (61–75% reduction in the number of plants attacked, 58–78% reduction in the number of larvae found per plant) as well as for the third generation (69–97% and 70–98% reduction, respectively). By plotting the amount of the antagonist remaining on the dispensers after 40–45 days of exposure with time, the mean release rate of the compound was calculated to be 2.2%/day in 2004, 1.95%/day in 2005, and 2.1%/day in 2006, with 26% of the initial compound remaining after 20 days of experimentation. The emission rate appears to cover the flight of the most damaging second generation of both insects. Prospects of using trifluoromethyl ketones as new potential agents for pest control are also outlined. [ABSTRACT FROM AUTHOR]

Devices designed for mechanical pain threshold studies are often difficult to implement. The purpose of this study was to investigate a simple tool based on calibrated forceps to induce quantifiable mechanical stimulation in the rat on a linear scale. The most suitable protocol was tested by determining the effects of 3 repetitive measurements on both hind paws, respectively, during long-term (9 days), mid-term (1 day), and short-term (2 hours). Only threshold increase related to weight gain over long-term was observed, suggesting that moderate rat training can be used. The capacity of the device to reveal hyperalgesia was tested in a model of carrageenan-induced inflammation in the hind paw. The hyperalgesia was maximal 6 hours after carrageenan injection and progressively decreased. Similar, although more variable, responses were observed with von Frey filaments. Morphine-induced analgesia resulted in a dose-dependent increase of paw threshold. Tolerance to morphine administrated on a once daily schedule (10 mg/kg) during 5 days was revealed by a significant decrease in analgesia by day 3. Taken together, these results demonstrated accuracy of this device for easy, fast, and reproducible measure of mechanical pain threshold on rat limbs. Moreover, it allows the performance of rat testing with minimal constraint, which reduces data variability. PERSPECTIVE: The calibrated forceps is an easy to use device well-suited to rapidly test mechanical pain threshold with accuracy. It is well-designed for preclinical behavioral screening of noxious or analgesic properties of molecules. [ABSTRACT FROM AUTHOR]

Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity., (© 2024. The Author(s).)

While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control., (© 2023. The Author(s).)

Food intake, which is a highly reinforcing behavior, provides nutrients required for survival in all animals. However, when fat and sugar consumption goes beyond the daily needs, it can favor obesity. The prevalence and severity of this health problem has been increasing with time. Besides covering nutrient and energy needs, food and in particular its highly palatable components, such as fats, also induce feelings of joy and pleasure. Experimental evidence supports a role of the striatal complex and of the mesolimbic dopamine system in both feeding and food-related reward processing, with the nucleus accumbens as a key target for reward or reinforcing-associated signaling during food intake behavior. In this review, we provide insights concerning the impact of feeding, including fat intake, on different types of receptors and neurotransmitters present in the striatal complex. Reciprocally, we also cover the evidence for a modulation of palatable food intake by different neurochemical systems in the striatal complex and in particular the nucleus accumbens, with a focus on dopamine, GABA and the opioid system., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9a R 185 H mutant mouse model using the CRISPR/Cas9 technology. The Scn9a R 185 H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9a R 185 H mice show a pain phenotype, suggesting that the SCN9A R 185 H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xue, Kremer, Muniz Moreno, Chidiac, Lorentz, Birling, Barrot, Herault and Gaveriaux-Ruff.)

The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) receives lateral habenula inputs and projects heavily to midbrain dopamine neurons. Midbrain dopamine and lateral habenula neurons participate in learning processes predicting the outcomes of actions, placing the tVTA in a critical location into prediction error pathways. tVTA GABA neurons show electrophysiological inhibition or activation after reward and aversive stimuli, respectively, and their predictive cues. tVTA molecular recruitment, however, is not elicited by all aversive stimuli. Indeed, precipitated opioid withdrawal, repeated footshocks or food restriction raise tVTA Fos expression, whereas various other unpleasant, stressful or painful stimuli does not elicit that molecular response. However, the basis of that difference remains unknown. In the present study, we tried to disentangle whether the tVTA c-Fos induction observed after food restriction was due to the aversive state of food restriction or to procedure-related reward prediction error. To this end, male Sprague-Dawley rats were food-restricted for 7-8 days. During this period, animals were handled and weighed every day before feeding. On the test day, rats underwent several behavioral procedures to explore the impact of food restriction and food-predictive cue exposure on tVTA c-Fos expression. We showed that food restriction per se was not able to recruit c-Fos in the tVTA. On the contrary, the food-predicting cues induced c-Fos locally in the absence of feeding, whereas the food-predicting cues followed by feeding evoked lower c-Fos expression. Overall, our results support the proposed involvement of the tVTA in reward prediction error., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) are regulated by phosphodiesterase (PDE) enzymes. Here, we studied the impact of PDE inhibitors (PDEi) in a mouse model of peripheral nerve injury induced by placing a cuff around the main branch of the sciatic nerve. Mechanical hypersensitivity, evaluated using von Frey filaments, was relieved by sustained treatment with the non-selective PDEi theophylline and ibudilast (AV-411), with PDE4i rolipram, etazolate and YM-976, and with PDE5i sildenafil, zaprinast and MY-5445, but not by treatments with PDE1i vinpocetine, PDE2i EHNA or PDE3i milrinone. Using pharmacological and knock-out approaches, we show a preferential implication of delta opioid receptors in the action of the PDE4i rolipram and of both mu and delta opioid receptors in the action of the PDE5i sildenafil. Calcium imaging highlighted a preferential action of rolipram on dorsal root ganglia non-neuronal cells, through PDE4B and PDE4D inhibition. Rolipram had anti-neuroimmune action, as shown by its impact on levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) in the dorsal root ganglia of mice with peripheral nerve injury, as well as in human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides. This study suggests that PDEs, especially PDE4 and 5, may be targets of interest in the treatment of neuropathic pain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Objective: Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. A number of preclinical studies have provided evidence for the involvement of cytokines, predominantly secreted by a variety of immune cells and by glial cells from the nervous system, in neuropathic pain conditions. Clinical trials and the use of anti-cytokine drugs in different neuropathic aetiologies support the relevance of cytokines as treatment targets. However, the use of such drugs, in particularly biotherapies, can provoke notable adverse effects. Moreover, it is challenging to select one given cytokine as a target, among the various neuropathic pain conditions. It could thus be of interest to target other proteins, such as growth factors, in order to act more widely on the neuroinflammation network. Thus, platelet-rich plasma (PRP), an autologous blood concentrate, is known to contain a natural concentration of growth factors and immune system messengers and is widely used in the clinical setting for tissue regeneration and repair., Database and Data Treatment: In the present review, we critically assess the current knowledge on cytokines in neuropathic pain by taking into consideration both human studies and animal models., Results: This analysis of the literature highlights the pathophysiological importance of cytokines. We particularly highlight the concept of time- and tissue-dependent cytokine activation during neuropathic pain conditions., Conclusion: Thus, direct or indirect cytokines modulation with biotherapies or growth factors appears relevant. In addition, we discuss the therapeutic potential of localized injection of PRP as neuropathic pain treatment by pointing out the possible link between cytokines and the action of PRP., Significance: Preclinical and clinical studies highlight the idea of a cytokine imbalance in the development and maintenance of neuropathic pain. Clinical trials with anticytokine drugs are encouraging but are limited by a 'cytokine candidate approach' and adverse effect of biotherapies. PRP, containing various growth factors, is a new therapeutic used in regenerative medicine. Growth factors can be also considered as modulators of cytokine balance. Here, we emphasize a potential therapeutic effect of PRP on cytokine imbalance in neuropathic pain. We also underline the clinical interest of the use of PRP, not only for its therapeutic effect but also for its safety of use., (© 2021 European Pain Federation - EFIC®.)

Central dopamine signaling regulates reward-related aspects of feeding behavior, and during diet-induced obesity dopamine receptor signaling is altered. Yet, the influence of dopamine signaling on the consumption of specific dietary components remains to be elucidated. We have previously shown that 6-hydroxydopamine-mediated lesions of dopamine neuron terminals in the lateral shell of the nucleus accumbens promotes fat intake in rats fed a multi-component free-choice high-fat high-sugar (fcHFHS) diet. It is however not yet determined which dopamine receptors are responsible for this shift towards fat preference. In this study, we assess the effects of D1-or D2 receptor acute inhibition in the lateral shell of the nucleus accumbens on fcHFHS diet consumption. We report that infusion of the D1 receptor antagonist SCH2 3390, but not the D2 receptor antagonist raclopride, promotes dietary fat consumption in male Sprague Dawley rats on a fcHFHS diet during 2 h after infusion. Furthermore, anatomical analysis of infusion sites revealed that the rostral region, but not the caudal region, of the lateral shell of the nucleus accumbens is sensitive to the D1 receptor inhibition effects on fat consumption. Our data highlight a role for D1 receptors in the rostral region of the lateral shell of the nucleus accumbens to control dietary fat consumption., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms, and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and importantly, connexins-transmembrane proteins involved in cell-cell communication-contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the antihyperalgesic effect of amitriptyline, a widely used antidepressant. In this study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. In addition, we showed that this potentiation was not due to pharmacokinetic interactions between the 2 drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenoceptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Dopamine influences food intake behavior. Reciprocally, food intake, especially of palatable dietary items, can modulate dopamine-related brain circuitries. Among these reciprocal impacts, it has been observed that an increased intake of dietary fat results in blunted dopamine signaling and, to compensate this lowered dopamine function, caloric intake may subsequently increase. To determine how dopamine regulates food preference we performed 6-hydroxydopamine (6-OHDA) lesions, depleting dopamine in specific brain regions in male Sprague Dawley rats. Food preference was assessed by providing the rats with free choice access to control diet, fat, 20% sucrose and tap water. Rats with midbrain lesions targeting the substantia nigra (which is also a model of Parkinson's disease) consumed fewer calories, as reflected by a decrease in control diet intake, but they surprisingly displayed an increase in fat intake, without change in the sucrose solution intake compared to sham animals. To determine which of the midbrain dopamine projections may contribute to this effect, we next compared the impact of 6-OHDA lesions of terminal fields, targeting the dorsal striatum, the lateral nucleus accumbens and the medial nucleus accumbens. We found that 6-OHDA lesion of the lateral nucleus accumbens, but not of the dorsal striatum or the medial nucleus accumbens, led to increased fat intake. These findings indicate a role for lateral nucleus accumbens dopamine in regulating food preference, in particular the intake of fat., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

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., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Parkinson's disease is a neurodegenerative disorder partly caused by the loss of the dopamine neurons of the nigrostriatal pathway. It is accompanied by motor as well as non-motor symptoms, including pain and depression. The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) is a GABAergic mesopontine structure that acts as a major inhibitory brake for the substantia nigra pars compacta (SNc) dopamine cells, thus controlling their neuronal activity and related motor functions. The present study tested the influence of suppressing this tVTA brake on motor and non-motor symptoms in a rat model of Parkinson's disease. Using behavioral approaches, we showed that male Sprague-Dawley rats with bilateral and partial 6-hydroxydopamine SNc lesion displayed motor impairments in the rotarod test, impairments that were no more present following a co-lesion of the tVTA. Using a larger set of behavioral tests, we then showed that such SNc lesion also led to non-motor symptoms, including lower body weight, lower mechanical nociceptive thresholds in the forceps test and lower thermal nociceptive thresholds in the incremented hot-plate test, and a decreased sucrose preference in a 2-bottle choice paradigm. The excitotoxic co-lesion of the tVTA led to compensation of body weight, mechanical nociceptive thresholds and anhedonia-like behavior. These findings illustrate the major influence that the tVTA exerts on the dopamine system, modulating the motor and non-motor symptoms related to a partial loss of dopamine cells., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)