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NEUROPHARMACOLOGY

(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel µ-Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties

Departments of Pharmacology (T.M.T., T.C., B.K., K.S., E.F., J.D.V.) and Molecular Pharmacology (H.-H.H., W.E., M.H.), and Preclinical Drug Development (U.J.), Grünenthal GmbH, Aachen, Germany; and Brains-on-Line, Groningen, The Netherlands (T.I.F.H.C.)

(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel µ-opioid receptor (MOR) agonist (K_i = 0.1 µM; relative efficacy compared with morphine 88% in a [³⁵S]guanosine 5'-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (K_i = 0.5 µM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED₅₀ values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the ₂-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

Address correspondence to: Dr. Thomas M. Tzschentke, Grünenthal GmbH, Preclinical Research and Development, Department of Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany. E-mail: thomas.tzschentke{at}grunenthal.com