Publications by authors named "Ipek Yalcin"

59 Publications

Enhanced analgesic cholinergic tone in the spinal cord in a mouse model of neuropathic pain.

Neurobiol Dis 2021 Apr 18;155:105363. Epub 2021 Apr 18.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France; University of Strasbourg Institute for Advanced Study (USIAS), 67000 Strasbourg, France. Electronic address:

Endogenous acetylcholine (ACh) is an important modulator of nociceptive sensory processing in the spinal cord. An increased level of spinal ACh induces analgesia both in humans and rodents while interfering with cholinergic signaling is allodynic, demonstrating that a basal tone of spinal ACh modulates nociceptive responses in naïve animals. The plasticity undergone by this cholinergic system in chronic pain situation is unknown, and the mere presence of this tone in neuropathic animals is controversial. We have addressed these issues in mice through behavioral experiments, histology, electrophysiology and molecular biology, in the cuff model of peripheral neuropathy. Our behavior experiments demonstrate the persistence, and even increased impact of the analgesic cholinergic tone acting through nicotinic receptors in cuff animals. The neuropathy does not affect the number or membrane properties of dorsal horn cholinergic neurons, nor specifically the frequency of their synaptic inputs. The alterations thus appear to be in the neurons receiving the cholinergic signaling, which is confirmed by the fact that subthreshold doses of acetylcholinesterase (AChE) inhibitors in sham animals become anti-allodynic in cuff mice and by the altered expression of the β2 nicotinic receptor subunit. Our results demonstrate that endogenous cholinergic signaling can be manipulated to relieve mechanical allodynia in animal models of peripheral neuropathy. Until now, AChE inhibitors have mainly been used in the clinics in situations of acute pain (parturition, post-operative). The fact that lower doses (thus with fewer side effects) could be efficient in chronic pain conditions opens new avenues for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chronic pain continues to be the most common cause of disability that impairs the quality of life, accruing enormous and escalating socio-economic costs. A better understanding of the plasticity of spinal neuronal networks, crucially involved in nociceptive processing, could help designing new therapeutic avenues. We here demonstrate that chronic pain modifies the spinal nociceptive network in such a way that it becomes more sensitive to cholinergic modulations. The spinal cholinergic system is responsible for an analgesic tone that can be exacerbated by acetylcholinesterase inhibitors, a property used in the clinic to relief acute pain (child birth, post-op). Our results suggest that lower doses of acetylcholinesterases, with even fewer side effects, could be efficient to relieve chronic pain.
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http://dx.doi.org/10.1016/j.nbd.2021.105363DOI Listing
April 2021

Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice.

Pain 2021 Mar 24. Epub 2021 Mar 24.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France Theranexus, Lyon, France.

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.
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http://dx.doi.org/10.1097/j.pain.0000000000002276DOI Listing
March 2021

Mapping the living mouse brain neural architecture: strain-specific patterns of brain structural and functional connectivity.

Brain Struct Funct 2021 Apr 26;226(3):647-669. Epub 2021 Feb 26.

Department of Radiology, Medical Physics, Medical Center, Faculty of Medicine, University of Freiburg, Breisacher Straße 60a, 79106, Freiburg, Germany.

Mapping brain structural and functional connectivity (FC) became an essential approach in neuroscience as network properties can underlie behavioral phenotypes. In mouse models, revealing strain-related patterns of brain wiring is crucial, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ strains are two of the primary "genetic backgrounds" for modeling brain disease and testing therapeutic approaches. However, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises questions on whether the observed effects are pathology specific or depend on the genetic background of each strain. Here, we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice using Magnetic Resonance Imaging (MRI). We combined deformation-based morphometry (DBM), diffusion MRI and high-resolution fiber mapping (hrFM) along with resting-state functional MRI (rs-fMRI) and demonstrated brain-wide differences in the morphology and "connectome" features of the two strains. Essential inter-strain differences were depicted regarding the size and the fiber density (FD) within frontal cortices, along cortico-striatal, thalamic and midbrain pathways as well as genu and splenium of corpus callosum. Structural dissimilarities were accompanied by specific FC patterns, emphasizing strain differences in frontal and basal forebrain functional networks as well as hubness characteristics. Rs-fMRI data further indicated differences of reward-aversion circuitry and default mode network (DMN) patterns. The inter-hemispherical FC showed flexibility and strain-specific adjustment of their patterns in agreement with the structural characteristics.
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http://dx.doi.org/10.1007/s00429-020-02190-8DOI Listing
April 2021

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation.

Nat Commun 2021 02 18;12(1):1132. Epub 2021 Feb 18.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montréal, Canada.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.
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http://dx.doi.org/10.1038/s41467-021-21365-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892573PMC
February 2021

Depression in focus: Insights from animal and human data, from molecular to behavioural analyses.

Eur J Neurosci 2021 Jan 10;53(1):5-8. Epub 2021 Jan 10.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.

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http://dx.doi.org/10.1111/ejn.15101DOI Listing
January 2021

Long-lasting analgesic and neuroprotective action of the non-benzodiazepine anxiolytic etifoxine in a mouse model of neuropathic pain.

Neuropharmacology 2021 01 16;182:108407. Epub 2020 Nov 16.

Centre National de la Recherche Scientifique and University of Strasbourg, Institute for Cellular and Integrative Neuroscience (INCI), 67000, Strasbourg, France. Electronic address:

Neuropathic pain is frequently associated with anxiety and major depressive disorders, which considerably impact the overall patient experience. Favoring GABAergic inhibition through the pain matrix has emerged as a promising strategy to restore proper processing of nociceptive and affective information in neuropathic pain states. In this context, the non-benzodiazepine anxiolytic etifoxine (EFX), known to amplify GABAergic inhibition through positive modulation of GABA receptors and neurosteroidogenesis, presents several advantages. Therefore, we sought to investigate the preclinical therapeutic potential of EFX on the somatosensory and affective components of neuropathic pain. Here, we used a murine model in which neuropathic pain was induced by the implantation of a compressive cuff around the sciatic nerve (mononeuropathy). We showed that the intraperitoneal EFX treatment for five consecutive days (50 mg/kg) relieved mechanical allodynia in a sustained manner. Besides its effect on evoked mechanical hypersensitivity, EFX also alleviated aversiveness of ongoing pain as well as anxiodepressive-like consequences of neuropathic pain following cuff-induced mononeuropathy. This effect was also seen 12 weeks after induction of the neuropathy when allodynia was no longer present. Analgesic and neuroprotective actions of EFX were also seen by the absence of neuropathic pain symptoms if a second sciatic nerve constriction injury was applied to the contralateral hindpaw. Mass spectrometry analysis revealed a normalization of brainstem serotonin levels in EFX-treated animals and an increase in norepinephrine. This study suggests that EFX presents promising therapeutic potential for the relief of both somatosensory and affective consequences of neuropathic pain, a beneficial effect that is likely to involve monoamine descending controls.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108407DOI Listing
January 2021

Comorbidity of chronic pain and anxiodepressive disorders: Deciphering underlying brain circuits.

Neurosci Biobehav Rev 2020 08 30;115:131-133. Epub 2020 May 30.

Centre National de la Recherche Scientifique, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives UPR3212, 67000 Strasbourg, France; Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.neubiorev.2020.05.013DOI Listing
August 2020

Delta opioid receptors are essential to the antiallodynic action of Β-mimetics in a model of neuropathic pain.

Mol Pain 2020 Jan-Dec;16:1744806920912931

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.

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http://dx.doi.org/10.1177/1744806920912931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097867PMC
February 2021

Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Front Mol Neurosci 2019 14;12:324. Epub 2020 Feb 14.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.
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http://dx.doi.org/10.3389/fnmol.2019.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033630PMC
February 2020

Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway.

Prog Neuropsychopharmacol Biol Psychiatry 2020 06 25;100:109898. Epub 2020 Feb 25.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique et Université de Strasbourg, 67000 Strasbourg, France. Electronic address:

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until up to 72 h. Altogether, these findings provide insight into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109898DOI Listing
June 2020

How to study anxiety and depression in rodent models of chronic pain?

Eur J Neurosci 2021 Jan 11;53(1):236-270. Epub 2020 Feb 11.

Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1111/ejn.14686DOI Listing
January 2021

Depression and antidepressant action-from molecules to networks.

Cell Tissue Res 2019 Jul;377(1):1-4

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg Cedex, France.

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http://dx.doi.org/10.1007/s00441-019-03042-6DOI Listing
July 2019

The molecular neurobiology of chronic pain-induced depression.

Cell Tissue Res 2019 Jul 19;377(1):21-43. Epub 2019 Feb 19.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique et Université de Strasbourg, 67000, Strasbourg, France.

The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. The recent development of animal models accelerated the studies focusing on the underlying mechanisms of the chronic pain and depression/anxiety comorbidity. This review provides an overview of clinical and pre-clinical studies performed over the past two decades addressing the molecular aspects of the comorbid relationship of chronic pain and depression. We thus focused on the studies that investigated the molecular characteristics of the comorbid relationship between chronic pain and mood disorders, especially major depressive disorders, from the genetic and epigenetic point of view to key neuromodulators which have been shown to play an important role in this comorbidity.
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http://dx.doi.org/10.1007/s00441-019-03003-zDOI Listing
July 2019

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Mol Neurobiol 2019 Jun 4;56(6):4163-4174. Epub 2018 Oct 4.

Faculty of Biological and Environmental Sciences, University of Helsinki, P.O.Box 65, Viikinkaari 1, Helsinki, Finland.

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (NO), another NMDA-R (N-methyl-D-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of NO to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinase-markers of neuronal excitability-were upregulated during NO exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3β (glycogen synthase kinase 3β) became regulated only gradually upon NO discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3β signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of α-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3β signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.
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http://dx.doi.org/10.1007/s12035-018-1364-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505519PMC
June 2019

A Dual Noradrenergic Mechanism for the Relief of Neuropathic Allodynia by the Antidepressant Drugs Duloxetine and Amitriptyline.

J Neurosci 2018 11 24;38(46):9934-9954. Epub 2018 Sep 24.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France,

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and β adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain. In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.
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http://dx.doi.org/10.1523/JNEUROSCI.1004-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596240PMC
November 2018

Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain.

Eur J Neurosci 2018 09 20;48(5):2231-2246. Epub 2018 Aug 20.

Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France.

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.
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http://dx.doi.org/10.1111/ejn.14093DOI Listing
September 2018

Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences.

J Neurosci 2018 03 20;38(12):3102-3115. Epub 2018 Feb 20.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France,

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.3195-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596067PMC
March 2018

Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFα overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation.

Eur J Med Chem 2018 Mar 31;147:163-182. Epub 2018 Jan 31.

CNRS, Université de Strasbourg, UMR7200 Laboratoire d' Innovation Thérapeutique, 67401 Illkirch, France; Labex MEDALIS, 67000 Strasbourg, France. Electronic address:

4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro-inflammatory cytokines (TNFα and Il1β) was identified from a high-throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFα overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice. In particular, compound 12 proved to be active (5 mg/kg, ip) in both models.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.049DOI Listing
March 2018

Epigenetic regulation of the kappa opioid receptor gene by an insertion-deletion in the promoter region.

Eur Neuropsychopharmacol 2018 02 12;28(2):334-340. Epub 2018 Jan 12.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, 6875 LaSalle Boulevard, Verdun, Quebec, Canada H4H 1R3. Electronic address:

Preclinical and clinical studies have demonstrated that the kappa opioid receptor (KOR) regulates reward, hedonic tone and emotions. At therapeutic level, on-going clinical trials are assessing the potential of targeting the KOR for the management of depression, anxiety disorders and substance use disorders. However, genetic polymorphisms in the KOR gene that potentially contribute to its implication in these phenotypes have been poorly studied. Here we investigated an insertion-deletion in the promoter region of KOR (rs35566036), recently associated with alcohol addiction, in a cohort of depressed subjects who died by suicide, as well as psychiatrically healthy individuals. Focusing on 3 brain regions (anterior insula, anterior cingulate cortex, and mediodorsal thalamus), we characterized the functional impact of this structural variant on the expression and patterns of DNA methylation of the KOR gene, using qPCR and targeted Bisulfite-Sequencing, respectively. While there was no significant change in the expression of KOR as a function of the insertion-deletion, or as a function of disease status in any brain region, we found that this variant strongly determines DNA methylation in KOR promoter, leading to a significant decrease in methylation levels of 8 nearby CpG dinucleotides located approximately 500 base pairs upstream the transcription start site. In addition, our results suggest a possible association between the insertion-deletion and depression; however, this result should be tested in larger populations. In sum, in this study we uncovered an epigenetic mechanism potentially contributing to KOR dysfunction in carriers of the insertion-deletion.
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http://dx.doi.org/10.1016/j.euroneuro.2017.12.013DOI Listing
February 2018

A comparison of early and late treatments on allodynia and its chronification in experimental neuropathic pain.

Mol Pain 2018 Jan-Dec;14:1744806917749683. Epub 2017 Dec 6.

2 Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.

Background Surgeries causing nerve injury can result in chronic neuropathic pain, which is clinically managed by using antidepressant or anticonvulsant drugs. Currently, there is a growing interest for investigating preemptive treatments that would prevent this long-term development of neuropathic pain. Our aim was to compare analgesic drugs using two distinct treatment modalities: either treatment onset at surgery time or following a couple of weeks of neuropathic pain. Methods In male C57BL/6J mice, neuropathic pain was induced by cuffing the sciatic nerve, and allodynia was assessed using von Frey filaments. We tested the effect of anticonvulsants (gabapentin 10 mg/kg and carbamazepine 40 mg/kg), antidepressants (desipramine 5 mg/kg, duloxetine 10 mg/kg, and fluoxetine 10 mg/kg), dexamethasone (2 mg/kg), and ketamine (15 mg/kg). Drugs were injected daily or twice a day, starting either at surgery time or on day 25 postsurgery (15 days of treatment for antidepressants and 10 days for other drugs). Results Ketamine was the only effective treatment during the early postsurgical period. Although early anticonvulsant treatment was not immediately effective, it prevented chronification of allodynia. When treatments started at day 25 postsurgery, desipramine, duloxetine, and anticonvulsants suppressed the mechanical allodynia. Conclusions Our data show that allodynia measured in experimental neuropathic pain model likely results from a combination of different processes (early vs. late allodynia) that display different sensitivity to treatments. We also propose that early anticonvulsant treatment with gabapentin or carbamazepine may have a prophylactic effect on the chronification of allodynia following nerve injury.
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http://dx.doi.org/10.1177/1744806917749683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804997PMC
October 2018

Efferents of anterior cingulate areas 24a and 24b and midcingulate areas 24a' and 24b' in the mouse.

Brain Struct Funct 2018 May 6;223(4):1747-1778. Epub 2017 Dec 6.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, CNRS UPR3212, 5 rue Blaise Pascal, 67084, Strasbourg, France.

The anterior cingulate cortex (ACC), constituted by areas 25, 32, 24a and 24b in rodents, plays a major role in cognition, emotion and pain. In a previous study, we described the afferents of areas 24a and 24b and those of areas 24a' and 24b' of midcingulate cortex (MCC) in mice and highlighted some density differences among cingulate inputs (Fillinger et al., Brain Struct Funct 222:1509-1532, 2017). To complete this connectome, we analyzed here the efferents of ACC and MCC by injecting anterograde tracers in areas 24a/24b of ACC and 24a'/24b' of MCC. Our results reveal a common projections pattern from both ACC and MCC, targeting the cortical mantle (intracingulate, retrosplenial and parietal associative cortex), the non-cortical basal forebrain, (dorsal striatum, septum, claustrum, basolateral amygdala), the hypothalamus (anterior, lateral, posterior), the thalamus (anterior, laterodorsal, ventral, mediodorsal, midline and intralaminar nuclei), the brainstem (periaqueductal gray, superior colliculus, pontomesencephalic reticular formation, pontine nuclei, tegmental nuclei) and the spinal cord. In addition to an overall denser ACC projection pattern compared to MCC, our analysis revealed clear differences in the density and topography of efferents between ACC and MCC, as well as between dorsal (24b/24b') and ventral (24a/24a') areas, suggesting a common functionality of these two cingulate regions supplemented by specific roles of each area. These results provide a detailed analysis of the efferents of the mouse areas 24a/24b and 24a'/24b' and achieve the description of the cingulate connectome, which bring the anatomical basis necessary to address the roles of ACC and MCC in mice.
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http://dx.doi.org/10.1007/s00429-017-1585-xDOI Listing
May 2018

Isoflurane produces antidepressant effects and induces TrkB signaling in rodents.

Sci Rep 2017 08 10;7(1):7811. Epub 2017 Aug 10.

Neuroscience Center, University of Helsinki, P.O. Box 56, Helsinki, FI-00014, Finland.

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.
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http://dx.doi.org/10.1038/s41598-017-08166-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552878PMC
August 2017

Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression.

Biol Psychiatry 2017 09 14;82(5):370-379. Epub 2017 Feb 14.

Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg. Electronic address:

Background: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression.

Methods: Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown.

Results: Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression.

Conclusions: These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.
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http://dx.doi.org/10.1016/j.biopsych.2017.01.019DOI Listing
September 2017

Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights.

Neuroscience 2016 Dec 9;338:183-206. Epub 2016 Jul 9.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France. Electronic address:

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system. It is generally chronic and challenging to treat. The recommended pharmacotherapy for neuropathic pain includes the use of some antidepressants, such as tricyclic antidepressants (TCAs) (amitriptyline…) or serotonin and noradrenaline re-uptake inhibitors (duloxetine…), and/or anticonvulsants such as the gabapentinoids gabapentin or pregabalin. Antidepressant drugs are not acute analgesics but require a chronic treatment to relieve neuropathic pain, which suggests the recruitment of secondary downstream mechanisms as well as long-term molecular and neuronal plasticity. Noradrenaline is a major actor for the action of antidepressant drugs in a neuropathic pain context. Mechanistic hypotheses have implied the recruitment of noradrenergic descending pathways as well as the peripheral recruitment of noradrenaline from sympathetic fibers sprouting into dorsal root ganglia; and importance of both α2 and β2 adrenoceptors have been reported. These monoamine re-uptake inhibitors may also indirectly act as anti-proinflammatory cytokine drugs; and their therapeutic action requires the opioid system, particularly the mu (MOP) and/or delta (DOP) opioid receptors. Gabapentinoids, which target the voltage-dependent calcium channels α2δ-1 subunit, inhibit calcium currents, thus decreasing the excitatory transmitter release and spinal sensitization. Gabapentinoids also activate the descending noradrenergic pain inhibitory system coupled to spinal α2 adrenoceptors. Gabapentinoid treatment may also indirectly impact on neuroimmune actors, like proinflammatory cytokines. These drugs are effective against neuropathic pain both with acute administration at high dose and with repeated administration. This review focuses on mechanistic knowledge concerning chronic antidepressant treatment and gabapentinoid treatment in a neuropathic pain context.
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http://dx.doi.org/10.1016/j.neuroscience.2016.06.057DOI Listing
December 2016

Afferents to anterior cingulate areas 24a and 24b and midcingulate areas 24a' and 24b' in the mouse.

Brain Struct Funct 2017 04 18;222(3):1509-1532. Epub 2016 Aug 18.

Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, 5 rue Blaise Pascal, 67084, Strasbourg, France.

Areas 24a and 24b of the anterior cingulate cortex (ACC) play a major role in cognition, emotion and pain. While their connectivity has been studied in primate and in rat, a complete mapping was still missing in the mouse. Here, we analyzed the afferents to the mouse ACC by injecting retrograde tracers in the ventral and dorsal areas of the ACC (areas 24a/b) and of the midcingulate cortex (MCC; areas 24a'/b'). Our results reveal inputs from five principal groups of structures: (1) cortical areas, mainly the orbital, medial prefrontal, retrosplenial, parietal associative, primary and secondary sensory areas and the hippocampus, (2) basal forebrain, mainly the basolateral amygdaloid nucleus, the claustrum and the horizontal limb of the diagonal band of Broca, (3) the thalamus, mainly the anteromedial, lateral mediodorsal, ventromedial, centrolateral, central medial and reuniens/rhomboid nuclei, (4) the hypothalamus, mainly the lateral and retromammillary areas, and (5) the brainstem, mainly the monoaminergic centers. The neurochemical nature of inputs from the diagonal band of Broca and brainstem centers was also investigated by double-labeling, showing that only a part of these afferents were cholinergic or monoaminergic. Comparisons between the areas indicate that areas 24a and 24b receive qualitatively similar inputs, but with different densities. These differences are more pronounced when comparing the inputs to ACC's areas 24a/24b to the inputs to MCC's areas 24a'/24b'. These results provide a complete analysis of the afferents to the mouse areas 24a/24b and 24a'/24b', which shows important similarity with the connectivity of homologous areas in rats, and brings the anatomical basis necessary to address the roles of cingulate areas in mice.
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http://dx.doi.org/10.1007/s00429-016-1290-1DOI Listing
April 2017

Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli.

Neuropsychopharmacology 2017 02 29;42(3):638-648. Epub 2016 Jul 29.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.

The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.
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http://dx.doi.org/10.1038/npp.2016.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240171PMC
February 2017

The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system.

Mol Pain 2016 29;12. Epub 2016 Mar 29.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.

Background: Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain.

Results: Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in μ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia.

Conclusions: We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain.
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http://dx.doi.org/10.1177/1744806916633477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956392PMC
December 2016

Loss of inhibitory tone on spinal cord dorsal horn spontaneously and nonspontaneously active neurons in a mouse model of neuropathic pain.

Pain 2016 07;157(7):1432-1442

Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212, Strasbourg, France.

Plasticity of inhibitory transmission in the spinal dorsal horn (SDH) is believed to be a key mechanism responsible for pain hypersensitivity in neuropathic pain syndromes. We evaluated this plasticity by recording responses to mechanical stimuli in silent neurons (nonspontaneously active [NSA]) and neurons showing ongoing activity (spontaneously active [SA]) in the SDH of control and nerve-injured mice (cuff model). The SA and NSA neurons represented 59% and 41% of recorded neurons, respectively, and were predominantly wide dynamic range (WDR) in naive mice. Nerve-injured mice displayed a marked decrease in the mechanical threshold of the injured paw. After nerve injury, the proportion of SA neurons was increased to 78%, which suggests that some NSA neurons became SA. In addition, the response to touch (but not pinch) was dramatically increased in SA neurons, and high-threshold (nociceptive specific) neurons were no longer observed. Pharmacological blockade of spinal inhibition with a mixture of GABAA and glycine receptor antagonists significantly increased responses to innocuous mechanical stimuli in SA and NSA neurons from sham animals, but had no effect in sciatic nerve-injured animals, revealing a dramatic loss of spinal inhibitory tone in this situation. Moreover, in nerve-injured mice, local spinal administration of acetazolamide, a carbonic anhydrase inhibitor, restored responses to touch similar to those observed in naive or sham mice. These results suggest that a shift in the reversal potential for anions is an important component of the abnormal mechanical responses and of the loss of inhibitory tone recorded in a model of nerve injury-induced neuropathic pain.
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http://dx.doi.org/10.1097/j.pain.0000000000000538DOI Listing
July 2016

Antidepressant drug action--From rapid changes on network function to network rewiring.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 9;64:285-92. Epub 2015 Jun 9.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, FR-67084 Strasbourg Cedex, France.

There has been significant recent progress in understanding the neurobiological mechanisms of antidepressant treatments. The delayed-onset of action of monoamine-based antidepressant drugs have been associated to their ability to slowly increase synaptic plasticity and neuronal excitability via altering neurotrophic signaling (synthesis of BDNF and activation of its receptor TrkB), dematuration of GABAergic interneurons and inhibition of "breaks of plasticity". On the other hand, antidepressants rapidly regulate emotional processing that - with the help of heightened plasticity and appropriate rehabilitation - gradually lead to significant changes on functional neuronal connectivity and clinical recovery. Moreover, the discovery of rapid-acting antidepressants, most notably ketamine, has inspired interest for novel antidepressant developments with better efficacy and faster onset of action. Therapeutic effects of rapid-acting antidepressants have been linked with their ability to rapidly regulate neuronal excitability and thereby increase synaptic translation and release of BDNF, activation of the TrkB-mTOR-p70S6k signaling pathway and increased synaptogenesis within the prefrontal cortex. Thus, alterations in TrkB signaling, synaptic plasticity and neuronal excitability are shared neurobiological phenomena implicated in antidepressant responses produced by both gradually and rapid acting antidepressants. However, regardless of antidepressant, their therapeutic effects are not permanent which suggests that their effects on neuronal connectivity and network function remain unstable and vulnerable for psychosocial challenges.
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http://dx.doi.org/10.1016/j.pnpbp.2015.06.001DOI Listing
January 2016

The anterior cingulate cortex is a critical hub for pain-induced depression.

Biol Psychiatry 2015 Feb 13;77(3):236-245. Epub 2014 Aug 13.

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique. Electronic address:

Background: Besides chronic stress, chronic pain is a prevalent determinant for depression. Changes induced in specific brain regions by sustained pain may alter the processing of affective information, thus resulting in anxiodepressive disorders. Here, we compared the role of the anterior cingulate cortex (ACC) and the posterior insular cortex in the anxiodepressive, sensory, and affective aspects of chronic pain.

Methods: Neuropathic pain was induced by cuffing the right sciatic nerve of C57BL/6J mice. Lesions were performed by local injection of ibotenic acid and chronic activation of the ACC by optogenetic stimulation. Anxiodepressive-related behaviors were evaluated through the novelty suppressed feeding, marble burying, splash, and forced swimming tests. Mechanical thresholds were determined using von Frey filaments, and the relief of spontaneous pain was determined by using place conditioning.

Results: The ACC lesion prevented the anxiodepressive consequences of chronic pain without affecting the sensory mechanical allodynia. Conversely, the tonic or spontaneous pain and the anxiodepressive consequences of pain remained present after posterior insular cortex lesion, even though the mechanical allodynia was suppressed. Furthermore, optogenetic stimulation of the ACC was sufficient to induce anxiety and depressive-like behaviors in naïve animals.

Conclusions: Our results show that, at cortical level, the sensory component of chronic pain remains functionally segregated from its affective and anxiodepressive components. Spontaneous tonic pain and evoked allodynia can be experimentally dissociated. Furthermore, the ACC appears as a critical hub for mood disorders, including for the anxiodepressive consequences of chronic pain, and thus constitutes an important target for divulging the underlying mechanism.
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http://dx.doi.org/10.1016/j.biopsych.2014.08.004DOI Listing
February 2015