title: Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats.
abstract: Antidepressants, prescribed as first line treatment of neuropathic pain, have a limited efficacy and poorly tolerated side effects. Because recent studies pointed out the implication of astroglial connexins (Cx) in both neuropathic pain and antidepressive treatment, we investigated whether their blockade by mefloquine could modulate the action of the tricyclic antidepressant amitriptyline. Using primary cultures, we found that both mefloquine and amitriptyline inhibited Cx43-containing gap junctions, and that the drug combination acted synergically. We then investigated whether mefloquine could enhance amitriptyline efficacy in a preclinical model of neuropathic pain. Sprague-Dawley rats that underwent chronic unilateral constriction injury (CCI) to the sciatic nerve (SN) were treated with either amitriptyline, mefloquine or the combination of both drugs. Whereas acute treatments were ineffective, chronic administration of amitriptyline reduced CCI-SN-induced hyperalgesia-like behavior, and this effect was markedly enhanced by co-administration of mefloquine, which was inactive on its own. No pharmacokinetic interactions between both drugs were observed and CCI-SN-induced neuroinflammatory and glial activation markers remained unaffected by these treatments in dorsal root ganglia and spinal cord. Mechanisms downstream of CCI-SN-induced neuroinflammation and glial activation might therefore be targeted. Connexin inhibition in astroglia could represent a promising approach towards improving neuropathic pain therapy by antidepressants.
authors.affiliation: Theranexus, Lyon, France.|CIRB, Collège de France, Paris, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Jeanson
authors.affiliation: Theranexus, Lyon, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Duchêne
authors.affiliation: CHU Clermont-Ferrand, Service de Pharmacologie Médicale, Clermont-Ferrand, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Richard
authors.affiliation: INSERM U894 - CPN, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bourgoin
authors.affiliation: Theranexus, Lyon, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Picoli
authors.affiliation: CIRB, Collège de France, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ezan
authors.affiliation: Theranexus, Lyon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Mouthon
authors.affiliation: CIRB, Collège de France, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.affiliation: INSERM U894 - CPN, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.affiliation: Theranexus, Lyon, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Charvériat
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism* / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D000639:Amitriptyline