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Papers of the Week


Papers: 6 Apr 2019 - 12 Apr 2019


Animal Studies, Pharmacology/Drug Development


2019 Nov 01


Neuropharmacology


158

The highly selective dopamine DR antagonist, RVK4-40, attenuates oxycodone reward and augments analgesia in rodents.

Authors

Jordan CJ, Humburg B, Rice M, Bi G-H, You Z-B, Shaik A B, Cao J, Bonifazi A, Gadiano A, Rais R, Slusher B, Newman A H, Xi Z-X
Neuropharmacology. 2019 Nov 01; 158:107597.
PMID: 30974107.

Abstract

Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of RVK4-40, a highly selective dopamine (DA) D receptor (DR) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of RVK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with RVK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D 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 RVK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, RVK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with RVK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and RVK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest RVK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of RVK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway.