Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol

Abstract Tramadol, (1 RS ,2 RS )-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) in the raphe nucleus. We have previously demonstrated that pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine 1A/1B receptor antagonist, enhanced tramadol antinociception and that the selective 5-HT 1A agonist 8-Hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT) reduced it. These effects were related to the negative feedback control that regulates raphe region neurones. The current study examines the ability of the selective antagonist at somatodendritic 5-HT 1A receptors, N -{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}- N -(2-pyridinyl) cyclohexane carboxamide (WAY100635, 0.8 mg/kg), the selective antagonist at terminal 5-HT 1B receptors, N -[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′-biphenyl)-4-carboxamide (SB216641, 0.1–0.8 mg/kg) and the selective agonist at 5-HT 1B receptors, 1,4-tDihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5 H -pyrrolo[3,2- b ] pyridin-5-one (CP93129, 0.2–0.4 mg/kg), to modify the antinociceptive effect of 4–64 mg/kg of tramadol in the hot plate test in mice. The results show that 0.8 mg/kg of WAY100635 enhanced antinociceptive effect of tramadol while neither agonism nor antagonism at the 5-HT 1B receptor modifies it significantly at the doses tested. These results account for involvement of the somatodendritic 5-HT 1A receptors in the analgesic effect of tramadol and support the supraspinal interaction of serotonin and the opioid system in the regulation of pain.