Effect of the Norepinephrine Transporter (NET) Inhibition on μ-Opioid Receptor (MOR)-Induced Anti-nociception in a Bone Cancer Pain Model

Abstract

Abstract. Although norepinephrine transporter (NET) inhibition has an additional effect on mopioid 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 antinociceptive 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 a 1 -adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by a 1 -or a 2 -adrenoceptor antagonists, suggesting that neither a 1 -adrenoceptor-nor a 2 -adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MORmediated anti-nociception in bone cancer pain.

The Antinociceptive Effect of a Tapentadol‐Ketorolac Combination in a Mouse Model of Trigeminal Pain is Mediated by Opioid Receptors and ATP‐Sensitive K+ Channels

“…The present study demonstrated that tapentadol produces antinociception in both phases of the orofacial formalin test. This study agrees with previous reports showing that tapentadol produces antinociception when administered systemically in animal models Christoph et al, 2011;Bujalska-Zadro_ zny et al, 2015;Ono et al, 2014] including the orofacial formalin test [Lee et al, 2015]. Furthermore, in the present study a dose-related antinociceptive effect of ketorolac was observed in both phases of the orofacial formalin in agreement with previous observations [Miranda et al, 1993;L opez-Muñoz et al, 2004;Isiordia et al, 2010].…”

Assessment of the antinociceptive and ulcerogenic activity of the tapentadol–diclofenac combination in rodents

“…The present study shows that the systemic administration of tapentadol produces a dose‐dependent antinociceptive effect in a mouse model of visceral pain in agreement with other reports (Bujalska‐Zadrożny, Wolińska, Gąsińska, & Nagraba, ; Christoph, De Vry, Schiene, Tallarida, & Tzschentke, ; Ono et al, ; Schiene, De Vry, & Tzschentke, ) that included the acetic acid‐induced writhing test (Zapata‐Morales et al, ). Likewise, systemic diclofenac showed a dose‐dependent antinociceptive action in the acetic acid‐induced visceral pain assay in mice again in agreement with other reports (León‐Reyes, Castañeda‐Hernández, & Ortiz, ; Ortiz, ; Ortiz et al, ), that included the writhing test (Goh et al, ).…”

Multiple effectiveness aspects of tapentadol for moderate–severe cancer-pain treatment: an observational prospective study

“…In vivo studies have dissected TP-induced opioid and noradrenergic actions 28. Nevertheless, the precise mechanism underlying the effect of TP on NeP should be better explained 29…”