BIASED ΜU-OPIOID RECEPTOR AGONISTS ADMINISTERED INTO THE VENTRAL TEGMENTAL AREA MODULATE PHASIC DOPAMINE RELEASE IN RATS

Introduction: Opioid analgesics are widely used for the treatment of moderate to severe pain. However, their adverse effects have led to a search for safer and less addictive opioids. Biased agonists of the μ-opioid receptor (MOR) are proposed as such therapeutics due to their diminished side effects. In particular, the addictive potential of 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.
Aims: We aimed to demonstrate the effects of biased MOR agonists on phasic dopamine release in the forebrain.
Methods: 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. Dopamine was measured via a carbon-fiber microelectrode inserted into the nucleus accumbens (NAc) in response to the administration of non-selective MOR agonists (morphine, DAMGO) and biased MOR agonists: SR-17018, PZM21, FH210 and its analog, BR41.
Results: The non-selective agonists showed no effects on phasic dopamine release. Conversely, PZM21 and BR41 dose-dependently attenuated dopamine release in the NAc, with PZM21 being the most potent. Administration of both SR-17018 and FH210 also attenuated phasic dopamine release but only at low doses.
Conclusions: These findings suggest that biased MOR agonists significantly differ in their effects, PZM21 being unique among them, making it a potential candidate for a safer analgesic with lower addictive potential and possibly for the substitution treatment of opioid use disorder. Funding: NCN, UMO-2020/39/B/NZ7/03537.