The Tramadol Metabolite O-Desmethyl Tramadol Inhibits Substance P–Receptor Functions Expressed in Xenopus Oocytes

Abstract

Substance P (SP) acts as a neurotransmitter released from C fibers located within nociceptive primary afferent neurons into the spinal cord and mediates a part of the excitatory synaptic input to nociceptive neurons at this level (1). SP and its receptors (SPR) are widely distributed in the central and peripheral nervous systems (2). Several studies showed that pain sensitivity is altered in mice lacking the gene encoding SPR; a reduction in nociceptive responses to certain somatic and visceral noxious stimuli occurs in SPR knockout mice (3).SPR belongs to the family of Gq protein-coupled receptors that activate the protein kinase C (PKC) and Ca 2+-mobilization by stimulation of phospholipase C. Our recent reports have shown that the function of SPR is inhibited by volatile anesthetics and intravenous anesthetics. Halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR (4). Moreover, ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, whereas propofol had little effect on the currents in Xenopus oocytes expressing SPR (5). These results suggest that SPR is one of the targets of some anesthetics.O-Desmethyl tramadol (ODT) is one of the metabolites of analgesic, tramadol. Only ODT among these metabolites has been shown to have analgesic activity in mice and rats, as assessed by the tail-flick responses. Analgesic potency of ODT is 2 -4-times higher than that of tramadol (1, 3). In addition, ODT has more affinity for the μ-opioid receptor than does tramadol in biochemical receptor binding studies, although its chemical structure is quite similar to tramadol (1). There have been several reports suggesting that ODT, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca 2+-activated Cl − currents in oocytes expressing 5-HT 2C R, and inhibited the functions of NMDA receptors, but not those of glycine and GABA A receptors (6). We have previously reported in Xenopus oocytes expressing SPR that tramadol had little effect on the SP-induced Ca 2+ -actvivated Cl − currents (5). However, a recent report has shown that tramadol, given intraperitoneally or intravenously, produced significant inhibition of the biting behavior induced by intrathecal injection of SP (7). We have previously reported the different effects on the Gq-coupled muscarinic M 3 receptors (M 3 R) between ODT and tramadol: tramadol inhibited acetylcholine (ACh)-induced currents in oocytes expressing M 3 R, whereas ODT did not. In the report we suggest that ODT does not affect the M 3 Rmediated signaling in spite of having only a small difference in its structure compared with that of tramadol (8) National Cancer Center Research Institute, Tokyo 104-0045, Japan Received December 6, 2010; Accepted January 25, 2011 Abstract. Tramadol has been widely used as analgesic. O-Desmethyl tramadol (ODT) is one of the main metabolites of tramadol, having much greater analgesic potency than tramadol itself. Substance P receptors (SPR) are well known to modulate ...

Tramadol in Japanese Population: the Relative Contribution of M1 Metabolite as Assessed by <i>CYP</i>2<i>D</i>6</i>*10 Genotype

“…The explanation appears to be related to the fact that tramadol inhibits neuronal reuptake of norepinephrine and 5-HT in the same concentration range that it binds to -opioid receptors, so both mechanisms are activated simultaneously. Other sites have also been speculated to play some role (e.g., [5][6][7]).…”