This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Nakamura, M. Articles by Sata, T. Search for Related Content PubMed PubMed Citation Articles by Nakamura, M. Articles by Sata, T.

---

PAIN MEDICINE

The Effects of the Tramadol Metabolite O-Desmethyl Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M₁ or M₃ Receptors

Motohiro Nakamura, MD^*, Kouichiro Minami, MD, PhD^*, Yasuhito Uezono, MD, PhD, Takafumi Horishita, MD, PhD^*, Junichi Ogata, MD, PhD^*, Munehiro Shiraishi, MD, PhD^*, Takashi Okamoto, MD^*, Tadanori Terada, MD^*, and Takeyoshi Sata, MD, PhD^*

*Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan; and Department of Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 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 807-8555, Japan. Address e-mail to kminami{at}med.uoeh-u.ac.jp.

O-desmethyl tramadol is one of the main metabolites of tramadol. It has been widely used clinically and has analgesic activity. Muscarinic receptors are involved in neuronal functions in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets for analgesic drugs in the central nervous system. We have reported that tramadol inhibits the function of type-1 muscarinic (M₁) receptors and type-3 muscarinic (M₃) receptors, suggesting that muscarinic receptors are sites of action of tramadol. However, the effects of O-desmethyl tramadol on muscarinic receptor functions have not been studied in detail. In this study, we investigated the effects of O-desmethyl tramadol on M₁ and M₃ receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1–100 µM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M₁ receptors (half-maximal inhibitory concentration [IC₅₀] = 2 ± 0.6 µM), whereas it did not suppress ACh-induced currents in oocytes expressing the M₃ receptor. Although GF109203X, a protein kinase C inhibitor, increased the ACh-induced current, it had little effect on the inhibition of ACh-induced currents by O-desmethyl tramadol in oocytes expressing M₁ receptors. The inhibitory effect of O-desmethyl tramadol on M₁ receptor was overcome when the concentration of ACh was increased (K_D with O-desmethyl tramadol = 0.3 µM). O-desmethyl tramadol inhibited the specific binding of [³H]quinuclidinyl benzilate ([³H]QNB) to the oocytes expressed M₁ receptors (IC₅₀ = 10.1 ± 0.1 µM), whereas it did not suppress the specific binding of [³H]QNB to the oocytes expressed M₃ receptors. Based on these results, O-desmethyl tramadol inhibits functions of M₁ receptors but has little effect on those of M₃ receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.

This article has been cited by other articles:

				I.-W. Shin, J.-T. Sohn, K.-E. Park, K. C. Chang, J.-Y. Choi, H.-K. Lee, and Y.-K. Chung A supraclinical dose of tramadol stereoselectively attenuates endothelium-dependent relaxation in isolated rat aorta. Anesth. Analg., August 1, 2006; 103(2): 366 - 71, table of contents. [Abstract] [Full Text] [PDF]