Role of serotonin 5-HT1A and opioid receptors in the antiallodynic effect of tramadol in the chronic constriction injury model of neuropathic pain in rats

Rationale Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms. Objectives The present study was undertaken to evaluate the potential role of 5-HT_1A receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT_1A receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT_1A receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats. Results The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5–10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg). Conclusions These findings suggest the involvement of opioid and 5-HT_1A receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT_1A antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.