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      α2- and β2-Adrenoreceptor-Mediated Efficacy of the Atypical Antidepressant Agomelatine Combined With Gabapentin to Suppress Allodynia in Neuropathic Rats With Ligated Infraorbital or Sciatic Nerve

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          Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves has specific characteristics and responds differently to alleviating drugs at cephalic versus extracephalic level. This is especially true for tricyclic antidepressants currently used for alleviating neuropathic pain in humans which are less effective against cephalic neuropathic pain. Whether this also applies to the antidepressant agomelatine, with its unique pharmacological properties as MT 1/MT 2 melatonin receptor agonist and 5-HT 2B/5-HT 2C serotonin receptor antagonist, has been investigated in two rat models of neuropathic pain. Acute treatments were performed 2 weeks after unilateral chronic constriction (ligation) injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION), when maximal mechanical allodynia had developed in ipsilateral hindpaw or vibrissal pad, respectively, in Sprague–Dawley male rats. Although agomelatine (45 mg/kg i.p.) alone was inactive, co-treatment with gabapentin, at an essentially ineffective dose (50 mg/kg i.p.) on its own, produced marked anti-allodynic effects, especially in CCI-ION rats. In both CCI-SN and CCI-ION models, suppression of mechanical allodynia by ‘agomelatine + gabapentin’ could be partially mimicked by the combination of 5-HT 2C antagonist (SB 242084) + gabapentin, but not by melatonin or 5-HT 2B antagonist (RS 127445, LY 266097), alone or combined with gabapentin. In contrast, pretreatment by idazoxan, propranolol or the β 2 antagonist ICI 118551 markedly inhibited the anti-allodynic effect of ‘agomelatine + gabapentin’ in both CCI-SN and CCI-ION rats, whereas pretreatment by the MT 1/MT 2 receptor antagonist S22153 was inactive. Altogether these data indicate that ‘agomelatine + gabapentin’ is a potent anti-allodynic combination at both cephalic and extra-cephalic levels, whose action implicates α 2- and β 2-adrenoreceptor-mediated noradrenergic neurotransmission.

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          Most cited references 72

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          Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

          New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.
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            Descending control of pain.

             Mark J Millan (2002)
            Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
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              A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man


                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                07 June 2018
                : 9
                1INSERM U894, Centre de Psychiatrie et Neurosciences , Paris, France
                2Institut de Recherches Internationales Servier , Suresnes, France
                Author notes

                Edited by: Pascal Bonaventure, Janssen Research and Development, United States

                Reviewed by: James Daniel Pomonis, American Preclinical Services (APS), United States; Mélanie Kremer, UPR3212 Institut des Neurosciences Cellulaires et Intégratives (INCI), France

                *Correspondence: Michel Hamon, michel.hamon@

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2018 M’Dahoma, Poitevin, Dabala, Payan, Gabriel, Mocaër, Bourgoin and Hamon.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 8, Tables: 0, Equations: 0, References: 72, Pages: 17, Words: 0
                Funded by: Institut National de la Santé et de la Recherche Médicale 10.13039/501100001677
                Award ID: U894
                Funded by: Université Pierre et Marie Curie 10.13039/501100005737
                Funded by: Université Paris Descartes 10.13039/501100005413
                Original Research


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