The highly selective dopamine D₃R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents

Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R-VK4-40, a highly selective dopamine (DA) D₃ receptor (D₃R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R-VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R-VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D₃ antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R-VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R-VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R-VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R-VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R-VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R-VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway. This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.