Effect of the Norepinephrine Transporter (NET) inhibition on μ-opioid receptor (MOR)-induced anti-nociception in a bone cancer pain model

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 α1-adrenoceptor antagonists. the partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a mor antagonist,but not by α1- or α2-adrenoceptor antagonists,suggesting that neither α1-adrenoceptor- nor α2-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. © the japanese pharmacological society.