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What is the main mechanism of tramadol?

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Abstract

Tramadol is an analgesic that is used worldwide for pain, but its mechanisms of action have not been fully elucidated. The majority of studies to date have focused on activation of the μ-opioid receptor (μOR) and inhibition of monoamine reuptake as mechanisms of tramadol. Although it has been speculated that tramadol acts primarily through activation of the μOR, no evidence has revealed whether tramadol directly activates the μOR. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of ion channels and G protein-coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for tramadol. In particular, tramadol has been shown to affect GPCRs. Here, the effects of tramadol on GPCRs, monoamine transporters, and ion channels are presented with a discussion of recent research on the mechanisms of tramadol.

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References

  • Andurkar SV, Gendler L, Gulati A (2012) Tramadol antinociception is potentiated by clonidine through alpha(2)-adrenergic and I(2)-imidazoline but not by endothelin ET(A) receptors in mice. Eur J Pharmacol 683:109–115

    Article  CAS  PubMed  Google Scholar 

  • Bamigbade TA, Davidson C, Langford RM, Stamford JA (1997) Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 79:352–356

    Article  CAS  PubMed  Google Scholar 

  • Bannon AW, Decker MW, Curzon P, Buckley MJ, Kim DJ, Radek RJ, Lynch JK, Wasicak JT, Lin NH, Arnold WH, Holladay MW, Williams M, Arneric SP (1998a) ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization. J Pharmacol Exp Ther 285:787–794

    CAS  PubMed  Google Scholar 

  • Bannon AW, Decker MW, Kim DJ, Campbell JE, Arneric SP (1998b) ABT-594, a novel cholinergic channel modulator, is efficacious in nerve ligation and diabetic neuropathy models of neuropathic pain. Brain Res 801:158–163

    Article  CAS  PubMed  Google Scholar 

  • Basbaum AI (1999) Distinct neurochemical features of acute and persistent pain. Proc Natl Acad Sci U S A 96:7739–7743

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Butcher JW, De Felipe C, Smith AJ, Hunt SP, Paton JF (1998) Comparison of cardiorespiratory reflexes in NK1 receptor knockout, heterozygous and wild-type mice in vivo. J Auton Nerv Syst 69:89–95

    Article  CAS  PubMed  Google Scholar 

  • Cao T, Gerard NP, Brain SD (1999) Use of NK(1) knockout mice to analyze substance P-induced edema formation. Am J Physiol 277:R476–481

    CAS  PubMed  Google Scholar 

  • Caulfield MP, Birdsall NJ (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290

    CAS  PubMed  Google Scholar 

  • Dascal N (1987) The use of Xenopus oocytes for the study of ion channels. CRC Crit Rev Biochem 22:317–387

    Article  CAS  PubMed  Google Scholar 

  • De Koninck Y, Henry JL (1991) Substance P-mediated slow excitatory postsynaptic potential elicited in dorsal horn neurons in vivo by noxious stimulation. Proc Natl Acad Sci U S A 88:11344–11348

    Article  PubMed Central  PubMed  Google Scholar 

  • Desmeules JA, Piguet V, Collart L, Dayer P (1996) Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 41:7–12

    Article  CAS  PubMed  Google Scholar 

  • Driessen B, Reimann W (1992) Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 105:147–151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Driessen B, Reimann W, Giertz H (1993) Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 108:806–811

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Durieux ME (1996) Muscarinic signaling in the central nervous system. Recent developments and anesthetic implications. Anesthesiology 84:173–189

    Article  CAS  PubMed  Google Scholar 

  • Frink EJ Jr, Malan TP, Atlas M, Dominguez LM, DiNardo JA, Brown BR Jr (1992) Clinical comparison of sevoflurane and isoflurane in healthy patients. Anesth Analg 74:241–245

    Article  PubMed  Google Scholar 

  • Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B (1996) Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 46:1029–1036

    CAS  PubMed  Google Scholar 

  • Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 362:116–121

    Article  CAS  PubMed  Google Scholar 

  • Grunfeld JA, Tiedemann GJ, Westerman RA (1991) Chronic nicotine exposure enhances cutaneous axon reflexes in the rat. Neuroreport 2:421–424

    Article  CAS  PubMed  Google Scholar 

  • Gyermek L (1996) Pharmacology of serotonin as related to anesthesia. J Clin Anesth 8:402–425

    Article  CAS  PubMed  Google Scholar 

  • Halfpenny DM, Callado LF, Hopwood SE, Bamigbade TA, Langford RM, Stamford JA (1999) Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry. Br J Anaesth 83:909–915

    Article  CAS  PubMed  Google Scholar 

  • Hara K, Minami K, Sata T (2005) The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg 100:1400–1405

    Article  CAS  PubMed  Google Scholar 

  • Hennies HH, Friderichs E, Schneider J (1988) Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung 38:877–880

    CAS  PubMed  Google Scholar 

  • Heyer G, Hornstein OP, Handwerker HO (1991) Reactions to intradermally injected substance P and topically applied mustard oil in atopic dermatitis patients. Acta Derm Venereol 71:291–295

    CAS  PubMed  Google Scholar 

  • Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A (2006) The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Pharmacology 77:93–99

    Article  CAS  PubMed  Google Scholar 

  • Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K (2006) Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology 51:651–8

    Article  CAS  PubMed  Google Scholar 

  • Kroeze WK, Kristiansen K, Roth BL (2002) Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2:507–528

    Article  CAS  PubMed  Google Scholar 

  • Lee CR, McTavish D, Sorkin EM (1993) Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 46:313–340

    Article  CAS  PubMed  Google Scholar 

  • Marincsak R, Toth BI, Czifra G, Szabo T, Kovacs L, Biro T (2008) The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg 106:1890–1896

    Article  CAS  PubMed  Google Scholar 

  • Mayer ML, Westbrook GL (1987) The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 28:197–276

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Uezono Y (2006) Gq protein-coupled receptors as targets for anesthetics. Curr Pharm Des 12:1931–1937

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Minami M, Harris RA (1997a) Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. J Pharmacol Exp Ther 281:1136–1143

    CAS  PubMed  Google Scholar 

  • Minami K, Vanderah TW, Minami M, Harris RA (1997b) Inhibitory effects of anesthetics and ethanol on muscarinic receptors expressed in Xenopus oocytes. Eur J Pharmacol 339:237–244

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Gereau RW 4th, Minami M, Heinemann SF, Harris RA (1998) Effects of ethanol and anesthetics on type 1 and 5 metabotropic glutamate receptors expressed in Xenopus laevis oocytes. Mol Pharmacol 53:148–156

    CAS  PubMed  Google Scholar 

  • Minami K, Shiraishi M, Uezono Y, Ueno S, Shigematsu A (2002) The inhibitory effects of anesthetics and ethanol on substance P receptors expressed in Xenopus oocytes. Anesth Analg 94:79–83

    CAS  PubMed  Google Scholar 

  • Minami K, Ogata J, Horishita T, Shiraishi M, Okamoto T, Sata T, Shigematsu A (2004a) Intramuscular tramadol increases gastric pH during anesthesia. Can J Anaesth 51:545–548

    Article  PubMed  Google Scholar 

  • Minami K, Uezono Y, Shiraishi M, Okamoto T, Ogata J, Horishita T, Taniyama K, Shigematsu A (2004b) Analysis of the effects of halothane on Gi-coupled muscarinic M2 receptor signaling in Xenopus oocytes using a chimeric G alpha protein. Pharmacology 72:205–212

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Uezono Y, Sakurai T, Horishita T, Shiraishi M, Ueta Y (2007a) Effects of anesthetics on the function of orexin-1 receptors expressed in Xenopus oocytes. Pharmacology 79:236–242

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Uezono Y, Ueta Y (2007b) Pharmacological aspects of the effects of tramadol on G-protein coupled receptors. J Pharmacol Sci 103:253–260

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Sudo Y, Shiraishi S, Seo M, Uezono Y (2010) Analysis of the effects of anesthetics and ethanol on mu-opioid receptor. J Pharmacol Sci 112:424–431

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Sudo Y, Yokoyama T, Ogata J, Takeuchi M, Uezono Y (2011a) Sevoflurane inhibits the micro-opioid receptor function expressed in Xenopus oocytes. Pharmacology 88:127–132

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Yokoyama T, Ogata J, Uezono Y (2011b) The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes. J Pharmacol Sci 115:421–424

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y (2015) Micro-opioid receptor activation by tramadol and O-desmethyltramadol (M1). J Anesth 29:475–9

    Article  PubMed  Google Scholar 

  • Miyano K, Minami K, Yokoyama T, Ohbuchi K, Yamaguchi T, Murakami S, Shiraishi S, Yamamoto M, Matoba M, Uezono Y (2015) Tramadol and its metabolite M1 selectively suppress the activity of the transient receptor potential ankyrin 1, but not that of the transient receptor potential vanilloid 1. Anesth Analg 120:790–8

    Article  CAS  PubMed  Google Scholar 

  • Naguib M, Yaksh TL (1997) Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg 85:847–853

    CAS  PubMed  Google Scholar 

  • Nakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T (2005) The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors. Anesth Analg 101:180–186

    Article  CAS  PubMed  Google Scholar 

  • Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y (2004) The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg 98:1401–1406

    Article  CAS  PubMed  Google Scholar 

  • Okamoto T, Minami K, Uezono Y, Ogata J, Shiraishi M, Shigematsu A, Ueta Y (2003) The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes. Anesth Analg 97:104–110

    Article  CAS  PubMed  Google Scholar 

  • Oliva P, Aurilio C, Massimo F, Grella A, Maione S, Grella E, Scafuro M, Rossi F, Berrino L (2002) The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 445:179–185

    Article  CAS  PubMed  Google Scholar 

  • Özdoğan UK, Lähdesmäki J, Scheinin M (2006) The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene. Eur J Pharmacol 529(1–3):105–13

    Article  PubMed  Google Scholar 

  • Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285

    CAS  PubMed  Google Scholar 

  • Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N (1993) Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 267:331–340

    CAS  PubMed  Google Scholar 

  • Reimann W, Hennies HH (1994) Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol. Biochem Pharmacol 47:2289–2293

    Article  CAS  PubMed  Google Scholar 

  • Roberts RG, Stevenson JE, Westerman RA, Pennefather J (1995) Nicotinic acetylcholine receptors on capsaicin-sensitive nerves. Neuroreport 6:1578–1582

    Article  CAS  PubMed  Google Scholar 

  • Sagata K, Minami K, Yanagihara N, Shiraishi M, Toyohira Y, Ueno S, Shigematsu A (2002) Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg 94:901–906

    Article  CAS  PubMed  Google Scholar 

  • Sawynok J, Reid AR, Liu J (2013) Spinal and peripheral adenosine A(1) receptors contribute to antinociception by tramadol in the formalin test in mice. Eur J Pharmacol 714:373–378

    Article  CAS  PubMed  Google Scholar 

  • Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A (2002) The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors. Anesth Analg 95:1269–1273

    Article  CAS  PubMed  Google Scholar 

  • Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A (2001) Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther 299:255–260

    CAS  PubMed  Google Scholar 

  • Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I (2002) Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha 7 receptors. Br J Pharmacol 136:207–216

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Steen KH, Reeh PW (1993) Actions of cholinergic agonists and antagonists on sensory nerve endings in rat skin, in vitro. J Neurophysiol 70:397–405

    CAS  PubMed  Google Scholar 

  • Wess J (1996) Molecular biology of muscarinic acetylcholine receptors. Crit Rev Neurobiol 10:69–99

    Article  CAS  PubMed  Google Scholar 

  • Xu XJ, Dalsgaard CJ, Wiesenfeld-Hallin Z (1992) Spinal substance P and N-methyl-D-aspartate receptors are coactivated in the induction of central sensitization of the nociceptive flexor reflex. Neuroscience 51:641–648

    Article  CAS  PubMed  Google Scholar 

  • Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, Konig M, Palkovits M, Mezey E (1998) Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci U S A 95:2630–2635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zoli M, Le Novere N, Hill JA Jr, Changeux JP (1995) Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and peripheral nervous systems. J Neuroscience 15:1912–1939

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Emergency Life Saving and Technique Tokyo, 4-5 Minamiosawa, Hachioji, Tokyo, 192-0364, Japan

    Kouichiro Minami & Junichi Ogata

  2. Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan

    Kouichiro Minami, Junichi Ogata & Yasuhito Uezono

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  1. Kouichiro Minami
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  2. Junichi Ogata
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  3. Yasuhito Uezono
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Correspondence to Kouichiro Minami.

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Minami, K., Ogata, J. & Uezono, Y. What is the main mechanism of tramadol?. Naunyn-Schmiedeberg's Arch Pharmacol 388, 999–1007 (2015). https://doi.org/10.1007/s00210-015-1167-5

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  • DOI: https://doi.org/10.1007/s00210-015-1167-5

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