title: Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain.
abstract: Neuropathic pain in diabetic patients is a common distressing symptom and remains a challenge for analgesic treatment. Selective inhibition of pathological pain sensation without modification of normal sensory function is a primary aim of analgesic treatment in chronic neuropathic pain. Tapentadol is a novel analgesic with two modes of action, mu-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition. Mice were rendered diabetic by means of streptozotocin, and neuropathic hyperalgesia was assessed in a 50 degrees C hot plate test. Normal nociception was determined in control mice. Tapentadol (0.1-1mg/kg i.v.) and morphine (0.1-3.16 mg/kg i.v.) dose-dependently attenuated heat-induced nociception in diabetic animals with full efficacy, reaching >80% at the highest doses tested. Tapentadol was more potent than morphine against heat hyperalgesia, with ED(50) (minimal effective dose) values of 0.32 (0.316) and 0.65 (1)mg/kg, respectively. Non-diabetic controls did not show significant anti-nociception with tapentadol up to the highest dose tested (1mg/kg). In contrast, 3.16 mg/kg morphine, the dose that resulted in full anti-hyperalgesic efficacy under diabetic conditions, produced significant anti-nociception in non-diabetic controls. Selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the treatment of chronic neuropathic pain when compared with classical opioids, such as morphine. It is hypothesized that this superior efficacy profile of tapentadol is due to simultaneous activation of MOR and inhibition of NA reuptake.
authors.affiliation: Global Preclinical Research and Development, Grünenthal GmbH, Aachen, Germany. thomas.christoph@grunenthal.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D000077432:Tapentadol; D016896:Treatment Outcome
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000701:Analgesics, Opioid; D010636:Phenols; D009020:Morphine; D000077432:Tapentadol