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Research ArticleNEUROPHARMACOLOGY

Inhibition by Tramadol of Muscarinic Receptor-Induced Responses in Cultured Adrenal Medullary Cells and in Xenopus laevis Oocytes Expressing Cloned M1Receptors

Munehiro Shiraishi, Kouichiro Minami, Yasuhito Uezono, Nobuyuki Yanagihara and Akio Shigematsu
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 255-260;
Munehiro Shiraishi
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Kouichiro Minami
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Yasuhito Uezono
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Nobuyuki Yanagihara
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Akio Shigematsu
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Abstract

Tramadol is a widely used, centrally acting analgesic, but its mechanisms of action are not completely understood. Muscarinic receptors are known to be involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. This study investigated the effects of tramadol on muscarinic receptors by using two different systems, i.e., a Xenopuslaevis oocyte expression system and cultured bovine adrenal medullary cells. Tramadol (10 nM–100 μM) inhibited acetylcholine-induced currents in oocytes expressing the M1receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. On the other hand, tramadol did not inhibit the current induced by AlF4−, a direct activator of GTP-binding protein. In cultured bovine adrenal medullary cells, tramadol (100 nM–100 μM) suppressed muscarine-induced cyclic GMP accumulation. Moreover, tramadol inhibited the specific binding of [3H]quinuclidinyl benzilate (QNB). Scatchard analysis showed that tramadol increases the apparent dissociation constant (Kd) value without changing the maximal binding (Bmax), indicating competitive inhibition. These findings suggest that tramadol at clinically relevant concentrations inhibits muscarinic receptor function via QNB-binding sites. This may explain the neuronal function and anticholinergic effect of tramadol.

Footnotes

  • This research was supported by Grants-in-Aid 11671532, 13671626, 12770851, 11770878, 12671515, 12671516, and 12770849 from the Ministry of Education, Science, and Culture of Japan; by a University of Occupational and Environmental Health Research Grant for Promotion of Occupational Health; by the Japan Research Foundation for Clinical Pharmacology; by the Uehara Memorial Foundation; and by the Kanehara-Ichiro Memorial Medical Foundation.

  • Abbreviations:
    CNS
    central nervous system
    QNB
    quinuclidinyl benzilate
    ACh
    acetylcholine
    PKC
    protein kinase C
    KRP
    Krebs-Ringer phosphate
    IBMX
    3-isobutyl-1-methylxanthine
    • Received April 20, 2001.
    • Accepted June 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleNEUROPHARMACOLOGY

Inhibition by Tramadol of Muscarinic Receptor-Induced Responses in Cultured Adrenal Medullary Cells and in Xenopus laevis Oocytes Expressing Cloned M1Receptors

Munehiro Shiraishi, Kouichiro Minami, Yasuhito Uezono, Nobuyuki Yanagihara and Akio Shigematsu
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 255-260;

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Research ArticleNEUROPHARMACOLOGY

Inhibition by Tramadol of Muscarinic Receptor-Induced Responses in Cultured Adrenal Medullary Cells and in Xenopus laevis Oocytes Expressing Cloned M1Receptors

Munehiro Shiraishi, Kouichiro Minami, Yasuhito Uezono, Nobuyuki Yanagihara and Akio Shigematsu
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 255-260;
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