title: The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes.
abstract: Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT(2C)R) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca(2+)-activated Cl(-) currents mediated by 5-HT(2C)R expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT(2C)R-mediated events. We also studied the effects of tramadol on [(3)H]5-HT binding to 5-HT(2C)R expressed in Xenopus oocytes, and found that it inhibited the specific binding of [(3)H]5-HT to 5-HT(2C)R. Scatchard analysis of [(3)H]5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT(2C)R function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT(2C)R, rather than via activation of the PKC pathway.
  
  
  CONCLUSIONS
  We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT(2C)R) expressed in Xenopus oocytes. Tramadol inhibited 5-HT(2C)R function and the specific binding of [(3)H]5-HT to 5-HT(2C)R in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT(2C)R might involve the competitive displacement of 5-HT binding to the 5-HT(2C)R.
authors.affiliation: Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Fukuoka 807-8555, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ogata
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Minami
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamoto
authors.forename: Munehiro
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Akio
authors.initials: A
authors.lastname: Shigematsu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ueta
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D008845:Microinjections; D009865:Oocytes; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D014147:Tramadol / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D000701:Analgesics, Opioid; D018118:Chloride Channels; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D012701:Serotonin; D014147:Tramadol; D011493:Protein Kinase C; D002118:Calcium