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Psychopharmacology (2007) 193:97105 DOI 10.1007/s00213-007-0761-8
ORIGINAL INVESTIGATION
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
Esther Berrocoso & M. Dolores De Benito &
Juan A. Mico
Received: 17 October 2006 / Accepted: 28 February 2007 / Published online: 29 March 2007 # Springer-Verlag 2007
AbstractRationale 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, nor-adrenaline and serotonin, by interfering with their re-uptake and release mechanisms.Objectives The present study was undertaken to evaluate the potential role of 5-HT1A receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT1A receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochlo-ride 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 (510 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-HT1A receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT1A antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.
Keywords Serotonin . Serotonin 5-HT1A receptors . Neuropathic pain . Tramadol . Opioid receptors . Rat
Introduction
Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is a centrally acting analgesic placed on step 2 pain ladder. Tramadol is a synthetic opioid that binds weakly to -opioid receptors (Hennies et al. 1988). In addition, tramadol is mainly metabolised by O-demethylation, and (+)-O-desmethyltramadol (M1) also binds to -opioid receptors with relatively high affinity (Raffa et al. 1993) participating to the analgesic activity. However, it has been shown that tramadol possesses a non-opioid mechanism that contributes to its pharmacological actions. It enhances the extraneuronal concentrations of the monoamine neurotransmitters noradrenaline and serotonin (5-HT) by...