title: Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.
abstract: 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.
authors.affiliation: Grünenthal GmbH, Global Preclinical Research and Development, Department of Pharmacology, Aachen, Germany. wolfgang.schroeder@grunenthal.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schröder
authors.forename: Jean De
authors.initials: JD
authors.lastname: Vry
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jahnel
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016014:Linear Models; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000077432:Tapentadol; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010636:Phenols; D017450:Receptors, Opioid, mu; D015016:Yohimbine; D009270:Naloxone; D000077432:Tapentadol; D009638:Norepinephrine