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.

Cortico-Amygdala-Striatal Activation by Modafinil/Flecainide Combination

“…Taking together, we demonstrated here that THN102 enhanced both locomotor activity and glucose metabolism in cortical and subcortical areas involved in the regulation of sleep-wake cycle and behaviors. Our results further support the hypothesis that astrocyte connexins are involved in pharmacological responses of psychoactive drugs such as modafinil ( Duchêne et al, 2016 ; Jeanson et al, 2016 ; Charvériat et al, 2017 ).…”

Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs

“…These findings are consistent with in vitro studies reporting a positive impact of antidepressant drugs of gap junction activity in rat primary cultures of cortical astrocytes and in human astrocytoma cell lines . Regarding hemichannels, a recent in vitro study has reported an unambiguous inhibitory action of SSRIs but also of Norepinephrine Reuptake Inhibitors and Serotonin‐Norepinephrine Reuptake Inhibitors on their functional activity with different degrees of efficacy …”

“…Indeed, the above‐mentioned studies examined the expression of Cx43 in the frontal cortex whereas we recently found that prolonged administration of fluoxetine reduced the expression of phosphorylated Cx43 in the hippocampus . It is also noteworthy, that a recent work established that tricyclics, SSRIs and Serotonin Norepinephrine Reuptake Inhibitors antidepressant drugs unambiguously reduce the activity of hemichannels . This would suggest that the beneficial effects of Cx43 inactivation reported herein rely on its ability to block the hemichannels rather than gap junctions.…”

“…Collectively, these results led us to propose (a) that the inactivation of astroglial Cx43 is sufficient to potentiate the antidepressant‐like effects of a sub‐active dose of fluoxetine and (b) that the vHP plays a critical role in this response. These findings strongly contrast with the fact that the acute or prolonged administration of various classes of antidepressant drugs including fluoxetine increases the expression of Cx43; as well as the activity of gap junctions . Such discrepancies could be attributed to the model used (in vivo vs in vitro / pathological vs non‐pathological conditions) or to regional differences.…”

Efficacy of THN201, a Combination of Donepezil and Mefloquine, to Reverse Neurocognitive Deficits in Alzheimer’s Disease

“…In this study, we postulate that Cx-based astroglial networks might modulate DPZ pharmacological effects, and use validated mouse models for assessing our hypothesis. Mefloquine (MEF) was selected as a pharmacological tool to modulate astroglial Cxs, as previously reported both in vitro and in vivo (Picoli et al, 2012(Picoli et al, , 2019Jeanson et al, 2016;Droguerre et al, 2019).…”