Preclinical Evaluation of Dual NOP/Mu Partial Agonists for Methamphetamine Use Disorder

Methamphetamine Use Disorder (MUD) lacks FDA-approved pharmacotherapy. This study investigates whether bifunctional partial agonists that target both mu opioid and nociceptin opioid peptide (NOP) receptors can effectively curb methamphetamine intake and relapse behavior. The authors hypothesize that compounds with enhanced NOP receptor engagement—designed to modulate the reward-reinforcing properties of mu-opioid activation—may offer a superior therapeutic profile compared to standard mu-agonist treatments.

The researchers evaluated two structurally related compounds, PPL-138 and PPL-143, which act as NOP/mu partial agonists. Using Sprague–Dawley rats, they employed a drug-versus-food choice paradigm, a translational model that tests whether a drug can reduce voluntary drug intake in the presence of a natural, non-drug alternative. They also examined the compounds' ability to suppress relapse in two preclinical models: prime-induced reinstatement (triggered by drug re-exposure) and cue-induced reinstatement (triggered by environmental stimuli associated with the drug).

PPL-138 proved to be the more promising candidate, significantly reducing both methamphetamine self-administration and prime-induced relapse. These effects were particularly robust in female rats, where the drug successfully shifted behavioral preference away from methamphetamine and toward food. In contrast, PPL-143, despite having a higher affinity for the NOP receptor, showed limited efficacy in these tasks. Crucially, neither compound succeeded in suppressing cue-induced relapse; both compounds actually increased drug-seeking behavior in the presence of drug-associated cues. Additionally, PPL-138 was shown to potentiate methamphetamine-induced locomotor activity, suggesting it may enhance stimulant-like physical responses even while reducing the addictive consumption of the drug itself.