title: Effect of the norepinephrine transporter (NET) inhibition on μ-opioid receptor (MOR)-induced anti-nociception in a bone cancer pain model.
abstract: Although norepinephrine transporter (NET) inhibition has an additional effect on μ-opioid receptor (MOR)-mediated anti-nociception in inflammatory and neuropathic pain, its effect on cancer pain is not well characterized. We investigated the additional effect of NET inhibition on MOR activation using a mouse femur bone cancer (FBC) pain model by comparing the anti-nociceptive effect of the dual-acting opioids tramadol and tapentadol and the clinically used MOR-targeted opioids oxycodone and morphine. The anti-nociceptive effects of subcutaneously administered opioids were assessed using the von-Frey filament test. Oxycodone (1 - 10 mg/kg) and morphine (5 - 50 mg/kg) dose-dependently exhibited potent anti-nociceptive effects, whereas tramadol (10 - 56 mg/kg) and tapentadol (10 - 30 mg/kg) exhibited partial effects. Rota-rod analyses of tapentadol at a higher dose (> 30 mg/kg) showed a significant decrease in motor coordination, which was partially recovered by pretreatment with MOR or α(1)-adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by α(1)- or α(2)-adrenoceptor antagonists, suggesting that neither α(1)-adrenoceptor- nor α(2)-adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MOR-mediated anti-nociception in bone cancer pain.
authors: Pain & Neurology, Medicinal Research Laboratories, Shionogi & Co., Ltd., Japan.
authors: Hiroko
authors: H
authors: Ono
authors: Atsushi
authors: A
authors: Nakamura
authors: Tomoe
authors: T
authors: Kanbara
authors: Kazuhisa
authors: K
authors: Minami
authors: Shunji
authors: S
authors: Shinohara
authors: Gaku
authors: G
authors: Sakaguchi
authors: Toshiyuki
authors: T
authors: Kanemasa
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008809:Mice, Inbred C3H; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009368:Neoplasm Transplantation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010098:Oxycodone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000378:metabolism* / Q000502:physiology; D000077432:Tapentadol; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000701:Analgesics, Opioid; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010636:Phenols; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; D014147:Tramadol; D009020:Morphine; D010098:Oxycodone; D000077432:Tapentadol