Differential inhibition of the diverse behavioural effects of mu-opioid receptor agonists by progressive receptor depletion

Mu-opioid receptor (MOR) agonists remain the mainstay treatment for severe acute pain but are limited by adverse effects including respiratory depression and constipation. Compounds with improved therapeutic profiles have been reported, and reduced intrinsic efficacy has been proposed as one factor contributing to greater separation between antinociceptive and adverse effects. To investigate the contribution of receptor reserve and intrinsic efficacy to the in vivo effects of opioid agonists, we used the pseudo-irreversible MOR antagonist methocinnamox (MCAM) to progressively deplete functional MORs and examined the effects of three MOR agonists-morphine, 7-OH mitragynine, and tianeptine-across multiple behavioural assays in mice. MCAM pretreatment inhibited agonist-induced effects in a dose-dependent manner across all assays. Lower doses of MCAM preferentially attenuated the antinociceptive, forced swim, and gastrointestinal effects of the lower-efficacy agonist 7-OH mitragynine, consistent with increased sensitivity of these behaviours to receptor depletion. In contrast, locomotor activation and respiratory depression induced by all three agonists were inhibited by similar MCAM doses, indicating comparable susceptibility to receptor depletion despite differences in intrinsic efficacy. Together, these findings suggest that differences in functional receptor reserve contribute to some, but not all, MOR-mediated behavioural outcomes. While reduced intrinsic efficacy and receptor reserve can partially explain separation between antinociception and certain adverse effects, additional ligand-dependent factors likely influence the expression of specific opioid-induced behaviours in vivo.