id_1011. PZM21, A G-PROTEIN BIASED Μ-OPIOID AGONIST, REDUCES OXYCODONE SEEKING IN PROTRACTED BUT NOT EARLY WITHDRAWAL IN RATS
Anna Ciejka1, Barbara Jędrzejewska2, Daria Krzysztofik1, Justyna Furso2, Ryszard Bugno3, Ryszard Przewłocki1, Wojciech Solecki2
1 Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Science
2 The Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Faculty of Management and Social Communication, Jagiellonian University, Cracow, Poland
3 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
INTRODUCTION: Opioid use disorder poses a pressing clinical problem, as currently available substitution therapies retain abuse liability. The G protein-biased µ-opioid receptor agonist PZM21 has been proposed as a safer alternative due to its reduced reinforcing properties. However, its effects on opioid-seeking behavior across different stages of withdrawal and relapse remain unexplored.
AIM(S): This study examined whether PZM21 modulates oxycodone-seeking during early (withdrawal day 1; WD1) and protracted (WD30) abstinence, and reinstatement, in rats.
METHOD(S): 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) intraperitoneal administration, they were tested for oxycodone-seeking during WD1 or WD30. After extinction training, reinstatement testing allowed active/inactive lever access (no drug infusion) and elicited oxycodone seeking via oxycodone prime, followed by PZM21 (10-40 mg/kg). In control tests, locomotor activity and anxiety-like behavior were assessed using the open field test.
RESULTS: During WD1, PZM21 did not alter overall active/inactive responding, though the time course showed a persistent reduction in active lever responding. In contrast, during WD30, PZM21 reduced active lever responding without affecting inactive lever presses. Both 10 and 40 mg/kg doses reduced oxycodone seeking during reinstatement tests. PZM21 did not affect locomotor activity or anxiety-like behavior.
CONCLUSIONS: PZM21 reduced oxycodone-seeking during protracted withdrawal and reinstatement—but not early withdrawal—without locomotor/anxiety effects, suggesting a stage-dependent effect and a promise for biased agonists in substitution/maintenance therapy.
FINANCIAL SUPPORT: National Science Centre, UMO-2020-39-B-NZ7-03537