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

Neuropharmacology. 2019 Nov 1:158:107597. doi: 10.1016/j.neuropharm.2019.04.003. Epub 2019 Apr 8.

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 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'.

Keywords: Brain-stimulation reward; D(3) receptor antagonist; Opioid analgesia; Oxycodone; R-VK4-40; Self-administration.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Dopamine Antagonists / pharmacology*
  • Dopaminergic Neurons / metabolism
  • Indoles / pharmacology*
  • Male
  • Nociception / drug effects*
  • Optogenetics
  • Oxycodone / pharmacology*
  • Piperazines / pharmacology*
  • Rats
  • Rats, Long-Evans
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Reinforcement Schedule
  • Reward*
  • Self Administration
  • Self Stimulation / drug effects*
  • Ventral Tegmental Area / metabolism

Substances

  • Analgesics, Opioid
  • Dopamine Antagonists
  • Drd3 protein, rat
  • Indoles
  • Piperazines
  • R-VK4-40
  • Receptors, Dopamine D3
  • Oxycodone