Analysis of Antinociception Produced by Positive Allosteric Modulators of the Mu‐Opioid Receptor

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Traditional opioids (e.g., morphine) provide analgesia by acting at the orthosteric site on the mu‐opioid receptor (MOR); however, G protein‐coupled receptor function can also be controlled by compounds acting at a separate (allosteric) site on the receptor. We have identified two compounds, BMS‐986122 and BMS‐986187, that bind to the allosteric site on the MOR and enhance the affinity and potency of MOR agonists in vitro. Thus, we hypothesized that BMS‐986122 and BMS‐986187 will produce antinociception by enhancing endogenous and exogenous opioid activity in vivo. Male and female mice were administered BMS‐986122, BMS‐986187, or vehicle via intraperitoneal injections (10 mg/kg; i.p.). Antinociception was assessed using the hot plate and warm water tail withdrawal tests. D,L‐methadone (10 mg/kg) produced antinociception on the tail withdrawal and hot plate tests. Co‐administration of BMS‐986187 did not enhance D,L‐methadone (3.2 mg/kg) antinociception on either test. However, a 30 min pretreatment of BMS‐986187 (10 mg/kg, i.p.) enhanced antinociception produced by an active dose of D,L‐methadone (10 mg/kg), but not an inactive dose (3.2 mg/kg), on the hot plate test. Intraperitoneal injection of both BMS‐986122 and BMS‐986187 alone produced near‐maximal antinociception on the tail withdrawal test for 2 hours that is likely caused by enhancement of endogenous opioid activity. Our data suggest complex interactions underlying antinociception produced by allosteric modulators of MOR that depend on several factors including dose, timing, and orthosteric agonist (methadone vs. endogenous opioid). Further, these data suggest that PAM‐mediated opioid antinociception affect pain processing at spinal and supraspinal levels.Support or Funding InformationRK was supported by T32 DA007268. Funding provided by R37 DA039997 (to JRT).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.