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PAIN MEDICINE

The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes

Junichi Ogata, MD^*, Kouichiro Minami, MD PhD^*, Yasuhito Uezono, MD PhD, Takashi Okamoto, MD^*, Munehiro Shiraishi, MD^*, Akio Shigematsu, MD PhD^*, and Yoichi Ueta, MD PhD

*Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan, the Second Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan, and the First Department of Physiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan

Address correspondence and reprint requests to Kouichiro Minami, MD, PhD, Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1–1, Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807–8555, Japan. Address email to kminami{at}med.uoeh-u.ac.jp

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_2CR) 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 Ca²⁺-activated Cl^– currents mediated by 5-HT_2CR 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_2CR-mediated events. We also studied the effects of tramadol on [³H]5-HT binding to 5-HT_2CR expressed in Xenopus oocytes, and found that it inhibited the specific binding of [³H]5-HT to 5-HT_2CR. Scatchard analysis of [³H]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_2CR function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT_2CR, rather than via activation of the PKC pathway.

IMPLICATIONS: We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT_2CR) expressed in Xenopus oocytes. Tramadol inhibited 5-HT_2CR function and the specific binding of [³H]5-HT to 5-HT_2CR in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT_2CR might involve the competitive displacement of 5-HT binding to the 5-HT_2CR.

This article has been cited by other articles:

				R. Marincsak, B. I. Toth, G. Czifra, T. Szabo, L. Kovacs, and T. Biro The Analgesic Drug, Tramadol, Acts as an Agonist of the Transient Receptor Potential Vanilloid-1 Anesth. Analg., June 1, 2008; 106(6): 1890 - 1896. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999