µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1).
Tramadol has been used as an analgesic for several decades. µ-Opioid receptors (µORs) are the major receptors that mediate the analgesic effects of opioids. Although µORs have been thought to be one of the sites of action of tramadol, there has been no report that directly proves whether tramadol is an agonist of μOR or not. In this study, we examined the effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of µORs using Xenopus oocytes expressing cloned human µORs. The effects of tramadol and M1 were evaluated using the Ca(2+)-activated Cl(-) current assay method for G(i/o)-protein-coupled receptors by using a µOR fused to G(qi5) (µOR-G(qi5)) in Xenopus oocytes. DAMGO [(D-Ala(2), N-MePhe(4), Gly(5)-ol)-enkephalin] evoked Cl(-) currents in oocytes expressing µOR-G(qi5) in a concentration-dependent manner. Tramadol and M1 also evoked Cl(-) currents in the oocytes expressing µOR-G(qi5); however, relatively higher concentrations (compared to DMAGO) were necessary to induce such currents. Tramadol and M1 had a direct effect on µORs expressed in Xenopus oocytes. Although the monoamine uptake system and several types of ligand-gated ion channels are thought to be one of the targets for tramadol, tramadol-induced antinociception may be mediated at least in part, by the direct activation of µORs.
Emergency Life Saving and Technique Tokyo, 4-5 Minamiosawa, Hachioji, Tokyo, 192-0364, Japan. kminami@med.uoeh-u.ac.jp.
Kouichiro
K
Minami
Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
Yuka
Y
Sudo
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Kanako
K
Miyano
Center of Fundamental Education, University of Kitakyushu, Fukuoka, Japan.
Robert S
RS
Murphy
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Yasuhito
Y
Uezono
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014147:Tramadol / Q000031:analogs & derivatives* / Q000494:pharmacology; D014982:Xenopus laevis
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C080580:O-demethyltramadol; D014147:Tramadol