BACKGROUND AND PURPOSE: β-Arrestin2 recruitment to μ-receptors may contribute to the development of opioid side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β-arrestin2 recruitment in favour of G-protein signalling. However, low efficacy β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to overexpression of μ-receptors. EXPERIMENTAL APPROACH: Efficacies and apparent potencies of DAMGO, morphine, PZM21 and TRV130 as stimulators of β-arrestin2 recruitment and inhibitors of cAMP accumulation were assessed in CHO cells stably expressing μ-receptors. Receptor availability was depleted through prior exposure of cells to the irreversible antagonist, β-FNA. We also examined whether μ-receptor availability influences TRV130 anti-nociception and/or tolerance using the tail withdrawal assay in wild-type C57BL/6 and μ+/- mice. KEY RESULTS: Morphine, PZM21 and TRV130 were partial agonists in the β-arrestin2 recruitment assay. Only TRV130 exhibited partial agonism in the cAMP assay. Exposure to β-FNA to reduce μ-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·kg-1 ) in wild-type mice, without tolerance after daily administration for 10 days. TRV130 caused similar anti-nociception in μ+/- mice, with marked tolerance on day 4 of injections. CONCLUSION AND IMPLICATIONS: Our findings emphasise the importance of receptor reserve when characterising μ-receptor agonists. Reduced receptor availability reveals that TRV130 is a partial agonist capable of tolerance, despite having limited efficacy for β-arrestin2 recruitment to the μ-receptor.
BACKGROUND AND PURPOSE: β-Arrestin2 recruitment to μ-receptors may contribute to the development of opioid side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β-arrestin2 recruitment in favour of G-protein signalling. However, low efficacy β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to overexpression of μ-receptors. EXPERIMENTAL APPROACH: Efficacies and apparent potencies of DAMGO, morphine, PZM21 and TRV130 as stimulators of β-arrestin2 recruitment and inhibitors of cAMP accumulation were assessed in CHO cells stably expressing μ-receptors. Receptor availability was depleted through prior exposure of cells to the irreversible antagonist, β-FNA. We also examined whether μ-receptor availability influences TRV130 anti-nociception and/or tolerance using the tail withdrawal assay in wild-type C57BL/6 and μ+/- mice. KEY RESULTS:Morphine, PZM21 and TRV130 were partial agonists in the β-arrestin2 recruitment assay. Only TRV130 exhibited partial agonism in the cAMP assay. Exposure to β-FNA to reduce μ-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·kg-1 ) in wild-type mice, without tolerance after daily administration for 10 days. TRV130 caused similar anti-nociception in μ+/- mice, with marked tolerance on day 4 of injections. CONCLUSION AND IMPLICATIONS: Our findings emphasise the importance of receptor reserve when characterising μ-receptor agonists. Reduced receptor availability reveals that TRV130 is a partial agonist capable of tolerance, despite having limited efficacy for β-arrestin2 recruitment to the μ-receptor.
Authors: Krishna K Sharma; Robert J Cassell; Yazan J Meqbil; Hongyu Su; Arryn T Blaine; Benjamin R Cummins; Kendall L Mores; David K Johnson; Richard M van Rijn; Ryan A Altman Journal: RSC Med Chem Date: 2021-08-16