Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.

Zhi-Bing You, Ph.D.

Featured Paper of the Month – April 2019.

Opioid use disorders are currently a serious health problem worldwide and yet prescription opioids remain as the most effective medications to treat pain. VK4-116, a highly selective dopamine D3 receptor antagonist, significantly inhibited acquisition of oxycodone self-administration behaviors and decreased oxycodone seeking in several rodent models. VK4-116 was also effective in a model of opioid-induced relapse and on diminishing the aversive effects of naloxone precipitated withdrawal. Notably, VK4-116 treatment had no effect on oxycodone-induced analgesia in the hot plate test. These results indicate that VK4-116 may be an effective non-opioid medication for the treatment of opioid use disorders, mitigating the development of dependence while preserving therapeutic usefulness of opioid analgesics.

Publication Information

You, Zhi-Bing; Bi, Guo-Hua; Galaj, Ewa; Kumar, Vivek; Cao, Jianjing; Gadiano, Alexandra; Rais, Rana; Slusher, Barbara S; Gardner, Eliot L; Xi, Zheng-Xiong; Newman, Amy Hauck

Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects. Journal Article

In: Neuropsychopharmacology, 2018, ISSN: 1740-634X (Electronic); 0893-133X (Linking).

Abstract | Links

@article{You:2018aa,

title = {Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.},

author = {Zhi-Bing You and Guo-Hua Bi and Ewa Galaj and Vivek Kumar and Jianjing Cao and Alexandra Gadiano and Rana Rais and Barbara S Slusher and Eliot L Gardner and Zheng-Xiong Xi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30555159},

doi = {10.1038/s41386-018-0284-5},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2018},

date = {2018-11-27},

journal = {Neuropsychopharmacology},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.},

abstract = {Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}