Opioids that act at the mu-opioid receptor (MOR) are the gold standard for pain management but can induce serious unwanted effects including addiction liability and respiratory depression. BMS-986122 is a positive allosteric modulator of MOR (MOR-PAM) that increases the actions of small molecule opioids and opioid peptides in vitro. In vivo, BMS-986122 enhances the action of endogenously released opioid peptides to provide MOR-mediated antinociception, but not constipation, reward, or respiratory depression. However, the effects of MOR-PAMs on the behavioral actions of opioid drugs such as morphine and fentanyl, have not been studied. Here we show that BMS-986122 enhances opioid drug-induced antinociception in assays for acute and inflammatory pain but not the adverse effects of constipation, respiratory depression measured by blood oxygen levels and respiration rate, or reward as determined by conditioned place preference. These data support the potential of MOR-PAMs as effective and safe opioid sparing agents for pain management.
Kochan et al. (Sun,) studied this question.
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