id_989. EFFECT OF TWO NOVEL BIASED Μ-OPIOID RECEPTOR AGONISTS ADMINISTERED INTO THE VENTRAL TEGMENTAL AREA ON PHASIC DOPAMINE RELEASE IN RATS
Jakub Duran1, Jakub Bilnicki2, Ryszard Bugno3, Ryszard Przewlocki4, Wojciech Solecki1
1 Department Of Neurobiology And Neuropsychology, Institute of Applied Psychology, Faculty of Management and Social Communication, Jagiellonian University, Kraków, Poland
2 Affective Cognitive Neuroscience Laboratory, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
3 Department Of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
4 Department Of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
INTRODUCTION: Opioid analgesics are widely used for the treatment of moderate to severe pain. However, their usage poses a risk of addiction and other adverse effects. The addictive potential of μ-opioid receptor (MOR) agonists is related to their reinforcing effect. This effect is associated with dopamine release, especially phasic release, which has been shown to promote drug seeking. This has led to a search for safer and less addictive opioids. Biased MOR agonists are proposed as such therapeutics due to their diminished side effects. One of such promising opioids is PZM21. In further search for potentially even more potent and safer opioids, PZM21 analogs, like FH210 were created. Subsequently, two novel biased MOR agonists with higher selectivity were developed: BR27 (a PZM21 analog) and BR41 (an FH210 analog).
AIM(S): We aimed to demonstrate the effects of biased MOR agonists on phasic dopamine release in the forebrain.
METHOD(S): We used fast-scan cyclic voltammetry in anesthetized male Sprague-Dawley rats to measure phasic dopamine release evoked by electrical stimulation of the ventral tegmental area. A carbon-fiber microelectrode was inserted into the nucleus accumbens (NAc) and used to measure phasic dopamine release in response to the administration of biased MOR agonists: PZM21, FH210, BR41, BR27.
RESULTS: PZM21, BR41 and BR27 dose-dependently attenuated dopamine release in the NAc, with PZM21 being the most potent. Administration of FH210 also attenuated phasic dopamine release but only at low doses.
CONCLUSIONS: These findings suggest that biased MOR agonists differ in their effects, with a higher selectivity not resulting in higher potency. PZM21 seems to be unique among the tested substances, making it a potential candidate for a safer analgesic with lower addictive potential.
FINANCIAL SUPPORT: NCN, UMO-2020/39/B/NZ7/03537