title: The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors.
abstract: Tramadol is a widely used analgesic, but its mechanism of action is not completely understood. Muscarinic receptors are 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. In this study, we investigated the effects of tramadol on type-3 muscarinic (M(3)) receptors using the Xenopus oocyte expression system. Tramadol (10 nM-100 micro M) inhibited acetylcholine-induced currents in oocytes expressing M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. Moreover, tramadol inhibited the specific binding sites of [(3)H]quinuclidinyl benzilate. These findings suggest that tramadol at clinically relevant concentrations inhibits M(3) function via quinuclidinyl benzilate-binding sites. This may explain the modulation of neuronal function and the anticholinergic effects of tramadol.
  
  
  CONCLUSIONS
  Muscarinic receptors are involved in neuronal function and are targets of analgesic drugs. We here report that tramadol inhibits type-3 muscarinic receptors function via quinuclidinyl benzilate-binding sites at clinically relevant concentrations. These findings may explain the modulation of neuronal function and the anticholinergic effects of tramadol.
authors.affiliation: Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807-8555, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Shiga
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Minami
authors.forename: Munehiro
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Osamu
authors.initials: O
authors.lastname: Murasaki
authors.forename: Muneshige
authors.initials: M
authors.lastname: Kaibara
authors.forename: Akio
authors.initials: A
authors.lastname: Shigematsu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003001:Cloning, Molecular; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics; D014147:Tramadol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D000701:Analgesics, Opioid; D007211:Indoles; D008301:Maleimides; D018727:Muscarinic Antagonists; D018075:RNA, Complementary; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D014147:Tramadol; D011813:Quinuclidinyl Benzilate; D007530:Isoflurane; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; C070515:bisindolylmaleimide I; D000109:Acetylcholine