Opioid use disorder (OUD) represents a debilitating psychiatric disorder that has reached epidemic proportions across the United States. Accumulating evidence suggests that selective inhibition of the M5 muscarinic acetylcholine receptor (mAChR) subtype may provide a novel target for the treatment of OUD. M5 is the only mAChR subtype expressed on midbrain dopamine (DA) cells and selective activation of M5 regulates mesolimbic DA reward circuitry. M5 knockout mice exhibit reduced morphine place preference with no effect on morphine-induced analgesia. Recently, we reported the successful optimization of the selective M5 negative allosteric modulator (NAM) ML375 that acts at a less highly conserved allosteric site on the receptor than the ACh binding site. In previous studies, we demonstrated that ML375 can attenuate cocaine self-administration in rodents. Here, we investigated the ability of ML375 to attenuate opioid self-administration without blocking opioid-induced analgesia in rats. Male Sprague-Dawley rats were trained to lever press for a 3 ug/kg/injection of remifentanil under a 10-response, fixed ratio schedule of i.v. drug injection during daily 1-h sessions. Following stable rates of remifentanil self-administration, a complete remifentanil dose-response curve was completed and the ability of ML375 to attenuate the reinforcing effects of remifentanil at each unit dose was then determined. Next, the effects of ML375 on reducing the reinforcing strength of remifentanil were assessed in rats responding under a progressive ratio (PR) schedule of reinforcement. Finally, the potential analgesic effects of ML375 alone and in combination with morphine were measured using a hot plate apparatus. Selective inhibition of M5 by ML375 produced a dose-related attenuation of remifentanil self-administration and reduction in the reinforcing strength of remifentanil under a PR schedule. ML375 also had no effect on morphine-induced analgesia within the dose range tested. These findings suggest that M5 NAMs may represent an exciting novel pharmacotherapy for the treatment of OUD.

Development of M5 muscarinic acetylcholine receptor negative allosteric modulators for the treatment of opioid use disorder

254th National Meeting (2017)

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