title: In vivo effect of tramadol on locus coeruleus neurons is mediated by alpha2-adrenoceptors and modulated by serotonin.
abstract: Tramadol is a centrally-acting analgesic endowed with opioid, noradrenergic and serotonergic properties. Various data suggest that, in addition to its analgesic effect, tramadol may have antidepressant and anxiolytic-like effects. This study investigates, through single-unit extracellular recording techniques, the in vivo effects of tramadol on locus coeruleus (LC) neurons and its possible effects on alpha(2)-adrenoceptors, opioid receptors and the 5-HT system. Tramadol produced a dose-dependent and complete inhibition of LC activity (ED(50)=2.1mg/kg). This inhibitory effect was prevented and reversed by the selective alpha(2)-adrenoceptor antagonist, idazoxan, but not by the opioid receptor antagonist, naloxone. The inhibition of the synthesis of 5-HT by p-chlorophenylalanine and the pre-administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT at 40microg/kg, caused a significant potentiation of the tramadol effect decreasing the ED(50) by 53% and 67% respectively. Lower doses of 8-OH-DPAT, of 1 and 4microg/kg, did not significantly modify the tramadol effect. In summary, the results indicate that tramadol elicits an inhibitory effect on LC neurons in vivo through alpha(2)-adrenoceptors. Moreover, this effect is modulated by the 5-HT system and particularly by 5-HT(1A) receptors.
authors.affiliation: Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Plaza Falla 9, E-11003 Cádiz, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Micó
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D005110:Extracellular Space / Q000502:physiology; D010134:Fenclonine / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014147:Tramadol / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D009292:Narcotic Antagonists; D009294:Narcotics; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D014147:Tramadol; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010134:Fenclonine