Positive Allosteric Modulation of the Mu Opioid Receptor Does Not Potentiate Opioid-Mediated Side Effects

Abstract ID 18014 Poster Board 210 Opioid therapeutics, such as morphine, that act at the mu-opioid receptor (MOR) are the clinical standard for managing pain. Although opioids are effective, their use leads to severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for safer alternatives to manage pain. One promising approach is to enhance the effects of the endogenous opioid system by the use of positive allosteric modulators (PAMs) of MOR. A known PAM, BMS-986122, enhances MOR agonist potency in cellular models. In mouse models, BMS-986122 promotes the antinociceptive activity of endogenous opioid peptides and exogenous opioid drugs in various pain assays. Moreover, at an effective antinociceptive dose in mice, BMS-986122 produces less severe adverse effects than morphine, as determined by measures of constipation, respiratory depression, and conditioned place preference. However, we do not yet know if the side effects of traditional exogenous opioids are increased by PAM modulation. Here we compare the ability of BMS-986122 to enhance the action of three structurally diverse opioid therapeutics, morphine, methadone, and fentanyl. We find that BMS-986122 increases the antinociceptive effects of the drugs in the warm water tail withdrawal and hot plate assays without promoting constipation, respiratory depression, or reward in CD1 male and female mice. Future work will assess the effects of BMS-986122 in chronic pain models. If BMS-986122 enhances MOR-mediated antinociception but not MOR-mediated adverse effects, the development of PAMs as standalone pain medications and opioid-sparing drugs will be a valuable approach to effective pain management. This work was funded by R37 DA039997. KEK was also supported by T32 GM007767 and a Rackham Predoctoral Fellowship.