(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel micro-opioid receptor (MOR) agonist (Ki = 0.1 microM; relative efficacy compared with morphine 88% in a [35S]guanosine 5'-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 microM 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 alpha2-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.
Department of Pharmacology, Grünenthal GmbH, Aachen, Germany. thomas.tzschentke@grunenthal.com
Thomas M
TM
Tzschentke
Thomas
T
Christoph
Babette
B
Kögel
Klaus
K
Schiene
Hagen-Heinrich
HH
Hennies
Werner
W
Englberger
Michael
M
Haurand
Ulrich
U
Jahnel
Thomas I F H
TI
Cremers
Elmar
E
Friderichs
Jean
J
De Vry
D000208:Acute Disease; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017551:Microdialysis; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000077432:Tapentadol
D000701:Analgesics, Opioid; D010636:Phenols; D017450:Receptors, Opioid, mu; D000077432:Tapentadol; D009638:Norepinephrine