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

Chloe J. Jordan, Bree Humburg, Myra Rice, Guo Hua Bi, Zhi Bing You, Anver Basha Shaik, Jianjing Cao, Alessandro Bonifazi, Alexandra Gadiano, Rana Rais, Barbara Slusher, Amy Hauck Newman, Zheng Xiong Xi

Research output: Contribution to journalArticle

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’.

Original languageEnglish (US)
Article number107597
JournalNeuropharmacology
Volume158
DOIs
StatePublished - Nov 1 2019

Fingerprint

Dopamine D3 Receptors
Oxycodone
Dopamine Antagonists
Reward
Analgesia
Opioid Analgesics
Rodentia
Self Stimulation
Prescriptions
Ventral Tegmental Area
Dopamine
Optogenetics
Somatoform Disorders
Self Administration
Dopaminergic Neurons
Pain Management
Locomotion
Analgesics
Appointments and Schedules
Therapeutics

Keywords

  • Brain-stimulation reward
  • D receptor antagonist
  • Opioid analgesia
  • Oxycodone
  • R-VK4-40
  • Self-administration

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

The highly selective dopamine D3R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents. / Jordan, Chloe J.; Humburg, Bree; Rice, Myra; Bi, Guo Hua; You, Zhi Bing; Shaik, Anver Basha; Cao, Jianjing; Bonifazi, Alessandro; Gadiano, Alexandra; Rais, Rana; Slusher, Barbara; Newman, Amy Hauck; Xi, Zheng Xiong.

In: Neuropharmacology, Vol. 158, 107597, 01.11.2019.

Research output: Contribution to journalArticle

Jordan, CJ, Humburg, B, Rice, M, Bi, GH, You, ZB, Shaik, AB, Cao, J, Bonifazi, A, Gadiano, A, Rais, R, Slusher, B, Newman, AH & Xi, ZX 2019, 'The highly selective dopamine D3R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents', Neuropharmacology, vol. 158, 107597. https://doi.org/10.1016/j.neuropharm.2019.04.003
Jordan, Chloe J. ; Humburg, Bree ; Rice, Myra ; Bi, Guo Hua ; You, Zhi Bing ; Shaik, Anver Basha ; Cao, Jianjing ; Bonifazi, Alessandro ; Gadiano, Alexandra ; Rais, Rana ; Slusher, Barbara ; Newman, Amy Hauck ; Xi, Zheng Xiong. / The highly selective dopamine D3R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents. In: Neuropharmacology. 2019 ; Vol. 158.
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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’.",
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AU - Bi, Guo Hua

AU - You, Zhi Bing

AU - Shaik, Anver Basha

AU - Cao, Jianjing

AU - Bonifazi, Alessandro

AU - Gadiano, Alexandra

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AU - Newman, Amy Hauck

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N2 - 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’.

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