Usefulness for the combination of G-protein- and β-arrestin-biased ligands of μ-opioid receptors: Prevention of antinociceptive tolerance

Background: mu-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although mu-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid-opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for mu-opioid receptors, TRV130, which has an antinociceptive effect without beta-arrestin-dependent mu-opioid receptor internalization, and its combination with fentanyl using mu-opioid receptor-expressing cells and mice. Results: In the present study, we confirmed that fentanyl produced a profound increase in beta-arrestin-2 recruitment accompanied by mu-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of beta-arrestin-2 or mu-opioid receptor internalization in mu-opioid receptor-expressing cells. Under these conditions, beta-arrestin-2 recruitment accompanied by mu-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cAMP formation by fentanyl in mu-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions: These findings provide evidence that activation of the G-protein-biased pathway through mu-opioid receptors can alter signaling in the beta-arrestin-2 pathway linked to the stimulation of mu-opioid receptors. Furthermore, the combination of G-protein-biased and beta-arrestin-biased ligands of mu-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.