DISTINCT EFFECTS OF G PROTEIN-BIASED MU-OPIOID RECEPTOR AGONISTS PZM21 AND SR-17018 ON OXYCODONE-SEEKING BEHAVIOR IN RATS

Introduction: Opioid use disorder remains a major clinical challenge, as current drugs used in substitution therapies retain addictive liability. Novel strategies that reduce abuse potential while preserving therapeutic efficacy are sought. G protein-biased mu-opioid receptor agonists, such as PZM21 and SR-17018, are promising candidates, with PZM21 showing no and SR-17018 limited reinforcing effects in conditioned place preference paradigms. However, their effects on opioid-seeking remain unexplored.
Aims: Here, we examined whether PZM21 and SR-17018 reduce oxycodone-seeking behaviour during withdrawal in rats.
Methods: Male Sprague–Dawley rats were trained to self-administer intravenous oxycodone under a fixed ratio schedule of reinforcement, in which active lever presses resulted in drug infusion. Following self-administration training, animals underwent abstinence and after PZM21 (10-40 mg/kg) or SR-17018 (2,5-10 mg/kg) intraperitoneal administration, were tested for oxycodone-seeking during early (withdrawal day 1, WD1) or protracted (withdrawal day 30, WD30) withdrawal. In control studies locomotor activity and anxiety-like behavior were assessed using the open field test.
Results: During WD1, PZM21 did not alter overall lever responding, although it transiently reduced active lever responding. Interestingly, during WD30, PZM21 (40 mg/kg) produced a sustained reduction in active lever presses without affecting inactive responding. In contrast, SR-17018 (10 mg/kg) increased active lever responding during WD1, but had no effect during WD30. Neither drug affected locomotion or anxiety-like behavior.
Conclusions: These findings demonstrate that PZM21, but not SR-17018, decreases oxycodone seeking and craving, thus suggesting its potential utility in opioid substitution/maintenance therapy. Funding: National Science Centre, UMO-2020-39-B-NZ7-03537.