title: Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol.
abstract: Tramadol, (1RS,2RS)-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-HT1A 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-HT1A 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-HT1B 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-HT1B receptors, 1,4-tDihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-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-HT1B receptor modifies it significantly at the doses tested. These results account for involvement of the somatodendritic 5-HT1A receptors in the analgesic effect of tramadol and support the supraspinal interaction of serotonin and the opioid system in the regulation of pain.
authors.affiliation: Pharmacology and Neuroscience Research Group (CTS-510), Department of Neuroscience, Faculty of Medicine, University of Cádiz, Plaza Fragela 9, 11003-Cádiz, Spain.
authors.forename: M Olga
authors.initials: MO
authors.lastname: Rojas-Corrales
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
authors.forename: Juan A
authors.initials: JA
authors.lastname: Micó
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014147:Tramadol / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D014147:Tramadol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide