Nakamura Motohiro, Minami Kouichiro, Uezono Yasuhito, Horishita Takafumi, Ogata Junichi, Shiraishi Munehiro, Okamoto Takashi, Terada Tadanori, Sata Takeyoshi
Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan.
Anesth Analg. 2005 Jul;101(1):180-6, table of contents. doi: 10.1213/01.ANE.0000154303.93909.A3.
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 (M(1)) receptors and type-3 muscarinic (M(3)) 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 M(1) and M(3) receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1-100 microM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M(1) receptors (half-maximal inhibitory concentration [IC(50)] = 2 +/- 0.6 microM), whereas it did not suppress ACh-induced currents in oocytes expressing the M(3) 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 M(1) receptors. The inhibitory effect of O-desmethyl tramadol on M(1) receptor was overcome when the concentration of ACh was increased (K(D) with O-desmethyl tramadol = 0.3 microM). O-desmethyl tramadol inhibited the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to the oocytes expressed M(1) receptors (IC(50) = 10.1 +/- 0.1 microM), whereas it did not suppress the specific binding of [(3)H]QNB to the oocytes expressed M(3) receptors. Based on these results, O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.
O-去甲基曲马多是曲马多的主要代谢产物之一。它已在临床上广泛应用且具有镇痛活性。毒蕈碱受体参与大脑和自主神经系统的神经元功能，并且这些受体作为中枢神经系统中镇痛药的靶点已受到广泛关注。我们曾报道曲马多抑制1型毒蕈碱（M(1)）受体和3型毒蕈碱（M(3)）受体的功能，这表明毒蕈碱受体是曲马多的作用位点。然而，O-去甲基曲马多对毒蕈碱受体功能的影响尚未得到详细研究。在本研究中，我们使用非洲爪蟾卵母细胞表达系统研究了O-去甲基曲马多对M(1)和M(3)受体的影响。O-去甲基曲马多（0.1 - 100微摩尔）抑制表达M(1)受体的卵母细胞中乙酰胆碱（ACh）诱导的电流（半数最大抑制浓度[IC(50)] = 2 ± 0.6微摩尔），而它不抑制表达M(3)受体的卵母细胞中ACh诱导的电流。尽管蛋白激酶C抑制剂GF109203X增加了ACh诱导的电流，但它对O-去甲基曲马多抑制表达M(1)受体的卵母细胞中ACh诱导电流的作用影响很小。当ACh浓度增加时，O-去甲基曲马多对M(1)受体的抑制作用被克服（O-去甲基曲马多存在时的解离常数[K(D)] = 0.3微摩尔）。O-去甲基曲马多抑制[³H]喹核醇基苯甲酸酯（[³H]QNB）与表达M(1)受体的卵母细胞的特异性结合（IC(50) = 10.1 ± 0.1微摩尔），而它不抑制[³H]QNB与表达M(3)受体的卵母细胞的特异性结合。基于这些结果，O-去甲基曲马多抑制M(1)受体的功能，但对M(3)受体的功能影响很小。本研究证明了O-去甲基曲马多对受体的分子作用，可能有助于解释其神经功能。
