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

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