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

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

Publication date: Apr 08, 2019

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.

Jordan, C.J., 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., and Xi, Z.X. The highly selective dopamine DR antagonist, RVK4-40, attenuates oxycodone reward and augments analgesia in rodents. 03363. 2019 Neuropharmacology.

Concepts Keywords
Analgesia Oxytrex
Analgesic Heroin
Antagonist Analgesic
Antinociceptive Oxycodone
Cre Brain stimulation reward
DA Morphine
DAT Morphinans
Dopamine Euphoriants
Dopamine Antagonist RTT
Dose Response Psychoactive drugs
DR Opioids
Locomotor Self administration
Mice Pain management
Neurons Pain
Neuropharmacology
Opioid
Opioids
Optogenetic
Oxycodone
Pain
Pain Management
Progressive
Receptor
Ventral Tegmental Area
VTA

Semantics

Type Source Name
disease MESH development
gene UNIPROT SLC6A3
gene UNIPROT IMPACT
disease DOID opioid abuse
disease MESH opioid abuse
disease DOID analgesia
drug DRUGBANK Oxycodone
drug DRUGBANK Dopamine

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *