id_982. SEX-DEPENDENT EFFECTS OF THE KAPPA-OPIOID RECEPTOR-BIASED AGONIST NALFURAFINE AND G PROTEIN-BIASED Μ-OPIOID RECEPTOR AGONIST PZM21 ON PHASIC DOPAMINE RELEASE IN RATS.
Magdalena Chodlewska1, Jakub Duran1, Daria Krzysztofik2, Jakub Bilnicki3, Ryszard Bugno4, Justyna Furso2, Ryszard Przewłocki2, Wojciech Solecki1
1 Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Faculty of Management and Social Communication, Jagiellonian University, Kraków, Poland
2 Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Science, Krakow, Poland
3 Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Faculty of Management and Social Communication, Jagiellonian University, Kraków, Poland
4 Department of Medicinal Chemistry, Institute of Applied Psychology, Faculty of Management and Social Communication, Jagiellonian University, Kraków, Poland
INTRODUCTION: Biological sex influences vulnerability to neuropsychiatric disorders, including opioid use disorder and mood disorders. Males and females show distinct behavioral responses to opioids, driven by differential modulation of mesolimbic dopamine signaling. μ-Opioid receptors (MORs), primary mediators of analgesia and reward, exhibit sex-dependent effects. Females show heightened sensitivity to MOR-mediated euphoria and reinforcement, increasing addiction liability, whereas males display stronger dysphoric responses to kappa-opioid receptor (KOR) activation, promoting negative affect and depressive-like states. Nalfurafine, a selective biased KOR agonist, preferentially activates G protein signaling while avoiding β-arrestin pathways, providing analgesia with reduced sedation, dysphoria, and aversive effects. PZM21, a biased MOR agonist, favors G protein signaling over β-arrestin recruitment, attenuating reinforcing properties and lowering addiction liability of conventional MOR agonists.
AIM(S): We investigated whether nalfurafine and PZM21 modulate phasic dopamine release in the mesolimbic system and whether these effects differ by sex.
METHOD(S): Phasic dopamine release was measured using fast-scan cyclic voltammetry in urethane-anesthetized male and female Sprague Dawley rats. Dopamine transients were evoked by electrical stimulation of the ventral tegmental area (VTA) and recorded in the nucleus accumbens (NAc). Nalfurafine and PZM21 were injected into the VTA to assess their impact on dopamine release.
RESULTS: Both nalfurafine and PZM21 attenuated phasic dopamine release in the NAc across sexes. However, the response in females was weaker than in males, indicating a diminished effect of these biased agonists. Suggesting reduced sensitivity to KOR and MOR agonism in the female brain.
CONCLUSIONS: These findings highlight sex dependent modulation of mesolimbic dopamine by biased KOR and MOR agonists, emphasizing sex as an important biological variable in opioid research with direct clinical implications.
FINANCIAL SUPPORT: National Science Centre: UMO-2020/39/B/NZ7/03537