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Neuropharmacology. 2019 Apr 8. pii: S0028-3908(18)30900-6. doi: 10.1016/j.neuropharm.2019.04.003. [Epub ahead of print]

The highly selective dopamine D3R antagonist, RVK4-40, attenuates oxycodone reward and augments analgesia in rodents.

Author information

1
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.
2
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA; Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD, 21205, USA.
3
Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD, 21205, USA.
4
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA. Electronic address: amy.newman@nih.gov.
5
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA. Electronic address: zxi@mail.nih.gov.

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) 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 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 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 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.

KEYWORDS:

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

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