Document Detail

Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.
MedLine Citation:
PMID:  20541444     Owner:  NLM     Status:  MEDLINE    
The novel analgesic tapentadol combines mu-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule and shows potent analgesia in various rodent models of pain. We analyzed the contribution of opioid and monoaminergic mechanisms to the activity of tapentadol in rat models of nociceptive and neuropathic pain. Antinociceptive efficacy was inferred from tail withdrawal latencies of experimentally naive rats using a tail flick test. Antihypersensitive efficacy was inferred from ipsilateral paw withdrawal thresholds toward an electronic von Frey filament in a spinal nerve ligation model of mononeuropathic pain. Dose-response curves of tapentadol (intravenous) were determined in combination with vehicle or a fixed dose (intraperitoneal) of the mu-opioid receptor antagonist naloxone (1mg/kg), the alpha2-adrenoceptor antagonist yohimbine (2.15 mg/kg), or the serotonin 5-HT(2A) receptor antagonist ritanserin (0.316 mg/kg). Tapentadol showed clear antinociceptive and antihypersensitive effects (>90% efficacy) with median effective dose (ED(50)) values of 3.3 and 1.9 mg/kg, respectively. While the antinociceptive ED(50) value of tapentadol was shifted to the right 6.4-fold by naloxone (21.2mg/kg) and only 1.7-fold by yohimbine (5.6 mg/kg), the antihypersensitive ED(50) value was shifted to the right 4.7-fold by yohimbine (8.9 mg/kg) and only 2.7-fold by naloxone (5.2mg/kg). Ritanserin did not affect antinociceptive or antihypersensitive ED(50) values of tapentadol. Activation of both mu-opioid receptors and alpha2-adrenoceptors contribute to the analgesic effects of tapentadol. The relative contribution is, however, dependent on the particular pain indication, as mu-opioid receptor agonism predominantly mediates tapentadol's antinociceptive effects, whereas noradrenaline reuptake inhibition predominantly mediates its antihypersensitive effects.
Wolfgang Schröder; Jean De Vry; Thomas M Tzschentke; Ulrich Jahnel; Thomas Christoph
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-11
Journal Detail:
Title:  European journal of pain (London, England)     Volume:  14     ISSN:  1532-2149     ISO Abbreviation:  Eur J Pain     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-23     Completed Date:  2010-12-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9801774     Medline TA:  Eur J Pain     Country:  England    
Other Details:
Languages:  eng     Pagination:  814-21     Citation Subset:  IM    
Copyright Information:
Copyright 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
Grünenthal GmbH, Global Preclinical Research and Development, Department of Pharmacology, Aachen, Germany.
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MeSH Terms
Adrenergic alpha-2 Receptor Antagonists / pharmacology
Analgesics, Opioid / pharmacology,  therapeutic use
Analysis of Variance
Dose-Response Relationship, Drug
Linear Models
Naloxone / pharmacology
Narcotic Antagonists / pharmacology
Neuralgia / drug therapy*,  metabolism*
Norepinephrine / metabolism*
Pain Measurement / drug effects
Phenols / pharmacology,  therapeutic use*
Rats, Sprague-Dawley
Receptors, Opioid, mu / agonists*
Yohimbine / pharmacology
Reg. No./Substance:
0/3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol; 0/Adrenergic alpha-2 Receptor Antagonists; 0/Analgesics, Opioid; 0/Narcotic Antagonists; 0/Phenols; 0/Receptors, Opioid, mu; 146-48-5/Yohimbine; 465-65-6/Naloxone; 51-41-2/Norepinephrine
Comment In:
Eur J Pain. 2010 Sep;14(8):781-3   [PMID:  20659810 ]

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