| First Author | Singleton S | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 8 | Pages | 1855-1868 |
| PubMed ID | 33555037 | Mgi Jnum | J:351000 |
| Mgi Id | MGI:7664700 | Doi | 10.1111/bph.15409 |
| Citation | Singleton S, et al. (2021) TRV130 partial agonism and capacity to induce anti-nociceptive tolerance revealed through reducing available mu-opioid receptor number. Br J Pharmacol 178(8):1855-1868 |
| abstractText | 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 (ED(50) : 0.33 mg.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. |
