Abstract
Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD.
Highlights
More than 2 million Americans currently suffer from substance use disorders that are related to prescription opioid pain relievers, including oxycodone (Oxycontin, Roxycodone, Oxecta ), and 500,000 are addicted to heroin (Substance Abuse and Mental Health Services Administration, 2013)
The Newman–Keuls post hoc test revealed the significant escalation of oxycodone self-administration that began from session 6 until session 15 compared with the first day of extended access (p < 0.01 for sessions 6–8; p < 0.001 for sessions 10–15; Figure 1A)
The reduction of oxycodone intake was mainly driven by the effect of VK4-116 in a subpopulation of rats that exhibited a high intake phenotype (i.e., High responders)
Summary
More than 2 million Americans currently suffer from substance use disorders that are related to prescription opioid pain relievers, including oxycodone (Oxycontin , Roxycodone , Oxecta ), and 500,000 are addicted to heroin (Substance Abuse and Mental Health Services Administration, 2013). Three treatments have been approved by the United States Food and Drug Administration for the treatment of opioid use disorder (OUD): methadone, buprenorphine, naltrexone, and their combination (e.g., Suboxone) or extended-release formulations (e.g., Vivitrol). Methadone and buprenorphine are effective in reducing opioid-induced mortality and maintaining patients in treatment, but important safety concerns and strict regulations because of their agonist properties at MORs have limited their use (National Academies of Sciences, Engineering, and Medicine, 2018). The recent introduction of extended-release naltrexone (Vivitrol) has slightly improved the use of naltrexone compared with previous formulations (Ndegwa et al, 2016). New treatments for OUD with better efficacy and without agonistic effects at the MOR need to be developed
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