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

Background and Purpose: β-arrestin2 recruitment to µ receptors may contribute to the development opioid analgesics 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 for β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to the 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 antinociception 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 being a partial agonist in vitro, TRV130 caused potent antinociception (ED50: 0.33 mg Kg-1) in wild type mice, without tolerance after daily administration for 10 days. TRV130 caused similar antinociception in µ+/- mice, with marked tolerance on day 4 of injections.

Conclusions and Implications: Our findings emphasise the importance of receptor reserve when characterising μ receptor agonists. Reduced receptor availability in vitro and in vivo reveals that TRV130 is a partial agonist capable of tolerance, despite having limited efficacy for β-arrestin2 recruitment to the μ receptor.