Papers of the Week

Opioid therapeutics, such as morphine, that act at the mu-opioid receptor (MOR) are the clinical standard for patients struggling to manage symptoms associated with pain. It is widely understood that although opioids are effective at treating pain, their use leads to the development of severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for a safer alternative to manage pain. One such alternative is to enhance the effects of the body's endogenous opioid system by positive allosteric modulation (PAM) of MOR. A known PAM, BMS-986122, enhances MOR agonist potency in cellular models and MOR agonist mediated antinociception in vivo. In addition, this PAM is active alone in a variety of mouse pain assays by promoting the activity of endogenous opioid peptides. Moreover, at an effective antinociceptive dose, BMS-986122 alone 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 how the overall pharmacology of opioids is affected by PAMs or if all opioid drugs are equally sensitive to PAM modulation. Here we compare the ability of BMS-986122 to enhance the action of three structurally diverse opioid drugs, morphine, methadone, and fentanyl, in an acute pain assay and in an assay examining respiratory depression using CD-1 male and female mice. We show that BMS-986122 increases the antinociceptive effects of the opioid therapeutics in the warm water tail withdrawal assay without promoting the ability of the drugs to lower blood oxygen levels or heart rate. Future work will assess the effects of BMS-986122 in additional acute and chronic pain models and with a more diverse group of opioids. If additional experiments support the concept that BMS-986122 enhances MOR-mediated antinociception but not MOR-mediated respiratory depression, this will validate the development of MOR-PAMs as standalone pain medications and support the use of PAMs as opioid-sparing drugs for the effective management of pain.