Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats

摘要: 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 astroglial connexins (Cx) in both pain antidepressive treatment, we investigated whether their blockade by mefloquine could modulate action tricyclic antidepressant amitriptyline. Using primary cultures, found that amitriptyline inhibited Cx43-containing gap junctions, drug combination acted synergically. We then enhance preclinical model pain. Sprague-Dawley rats underwent chronic unilateral constriction injury (CCI) to sciatic nerve (SN) were treated with either amitriptyline, or drugs. Whereas acute treatments ineffective, administration reduced CCI-SN-induced hyperalgesia-like behavior, this effect was markedly enhanced co-administration mefloquine, which inactive on its own. No pharmacokinetic interactions between drugs observed neuroinflammatory glial activation markers remained unaffected these dorsal root ganglia spinal cord. Mechanisms downstream neuroinflammation might therefore be targeted. Connexin inhibition astroglia represent promising approach towards improving therapy antidepressants.