TRV130 partial agonism and capacity to induce anti?nociceptive tolerance revealed through reducing available ??opioid receptor number

Background and Purpose ?-Arrestin2 recruitment to ?-receptors may contribute the development of opioid side effects. This possibility led TRV130 PZM21, opioids reportedly biased against ?-arrestin2 in favour G-protein signalling. However, low efficacy by PZM21 simply reflect partial agonism overlooked due overexpression ?-receptors. Experimental Approach Efficacies apparent potencies DAMGO, morphine, as stimulators inhibitors cAMP accumulation were assessed CHO cells stably expressing Receptor availability was depleted through prior exposure irreversible antagonist, ?-FNA. We also examined whether ?-receptor influences anti-nociception and/or tolerance using tail withdrawal assay wild-type C57BL/6 ?+/? mice. Key Results Morphine, agonists assay. Only exhibited Exposure ?-FNA reduce further limited revealed morphine be agonists. Despite having vitro, caused potent (ED50: 0.33 mg·kg?1) mice, without after daily administration for 10 days. similar with marked on day 4 injections. Conclusion Implications Our findings emphasise importance receptor reserve when characterising Reduced reveals that is a agonist capable tolerance, despite ?-receptor.