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

Abstract

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 MT1/MT2 melatonin receptor agonist and 5-HT2B/5-HT2C 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-HT2C antagonist (SB 242084) + gabapentin, but not by melatonin or 5-HT2B antagonist (RS 127445, LY 266097), alone or combined with gabapentin. In contrast, pretreatment by idazoxan, propranolol or the β2 antagonist ICI 118551 markedly inhibited the anti-allodynic effect of ‘agomelatine + gabapentin’ in both CCI-SN and CCI-ION rats, whereas pretreatment by the MT1/MT2 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 α2- and β2-adrenoreceptor-mediated noradrenergic neurotransmission.

The effectiveness of pregabalin with or without agomelatine in the treatment of chronic low back pain: a double-blind, placebo-controlled, randomized clinical trial

“…The study of Aydın et al revealed the curative effect of agomelatine on painful diabetic neuropathy in rats and suggested that these effects are mediated by rising synaptic catecholamine levels and through interactions with both α- and β-adrenoceptors [ 22 ]. The study of M’Dahoma et al revealed that co-administration of agomelatine and gabapentin is a potent anti-allodynic combination in neuropathic rats with the ligated infraorbital or sciatic nerve, which is medicated by α2- and β2-adrenoreceptor noradrenergic neurotransmission [ 23 ]. Considering neuropathic pain is a crucial component of CLBP, agomelatine might possibly alleviate CLBP symptoms.…”

<p>Role of Melatonin in the Regulation of Pain</p>

“…90 Interestingly, agomelatine, a melatonin analog, administration alone had no effect on mechanical allodynia induced by chronic constriction (ligation) injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION) rats but produced an anti-allodynic effect when combined with gabapentin. 91 However, in another study, agomelatine dosedependently decreased mechanical hypersensitivity in three neuropathic pain models (oxaliplatin, streptozocin, and CCI). 92 The analgesic effect of agomelatine remains controversial and needs to be validated.…”

“…60 In addition, agomelatine exhibits anti-allodynia through noradrenergic neurotransmission mediated by α 2 -adrenoceptors and β 2 -adrenoceptors. 91…”

PRECISE trial (Pain RElief Combination Intervention StratEgies): protocol for the clinical trial of a pregabalin–melatonin combination for fibromyalgia

“…Hypothesised superiority of a PGB-MLT combination is based on RCT data indicating that combinations of two mechanistically different treatments show superior efficacy vs either single agent 10-14 43 50-52 and also based on relevant evidence suggesting favourable antinociceptive interactions between these drugs. [53][54][55] Review of sleep outcomes, from RCTs of PGB for pain treatment, has revealed a positive benefit on disturbed sleep through a direct effect on sleep maintenance (ie, staying asleep). Exogenous administration of the pineal hormone, MLT, has been reported to reduce pain in both preclinical and clinical settings (including four fibromyalgia trials), in addition to other RCT evidence of efficacy for primary insomnia and delayed sleep phase syndrome (ie, falling asleep).…”