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Purpose of Review <p>This review explores the paradoxical effects of opioids, where reward (euphoria) and aversion (dysphoria) occur simultaneously during intoxication. The aim is to analyze the neural mechanisms, compare the paradoxical effect hypothesis with other addiction theories, and evaluate current and novel pharmacological treatments and animal models.</p> Recent Findings <p>Opioid intoxication causes initial euphoria, followed by dysphoria and agitation. Withdrawal symptoms include depression, anxiety, and high suicide rates. The paradoxical effect hypothesis posits that reward and aversion co-occur, disrupting brain homeostasis during intoxication. The mesolimbic dopamine system, the vagus nerve/area postrema, and kappa-opioid receptors contribute to reward and aversion. Current treatments (methadone, buprenorphine, naloxone) have limitations. Novel approaches target neuroinflammation, BDNF, glutamate, and the purinergic system to address brain disturbances.</p> Summary <p>A critical need for novel therapies manages restore brain homeostasis to effectively alleviate OUD symptoms. Preclinical studies provide implications for the development of novel treatments, impacting the development of new drugs in clinical respects.</p>

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Understanding Opioid Use Disorder: the Paradoxical Co-occurrence of Reward and Aversion during Intoxication

  • 期刊论文

  • 发表日期：

    2025年11月11日

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  • Andrew Chih Wei Huang,
  • Anna Kozłowska,
  • Chi-Wen Wu,
  • Cai-N Cheng

摘要

Purpose of Review

This review explores the paradoxical effects of opioids, where reward (euphoria) and aversion (dysphoria) occur simultaneously during intoxication. The aim is to analyze the neural mechanisms, compare the paradoxical effect hypothesis with other addiction theories, and evaluate current and novel pharmacological treatments and animal models.

Recent Findings

Opioid intoxication causes initial euphoria, followed by dysphoria and agitation. Withdrawal symptoms include depression, anxiety, and high suicide rates. The paradoxical effect hypothesis posits that reward and aversion co-occur, disrupting brain homeostasis during intoxication. The mesolimbic dopamine system, the vagus nerve/area postrema, and kappa-opioid receptors contribute to reward and aversion. Current treatments (methadone, buprenorphine, naloxone) have limitations. Novel approaches target neuroinflammation, BDNF, glutamate, and the purinergic system to address brain disturbances.

Summary

A critical need for novel therapies manages restore brain homeostasis to effectively alleviate OUD symptoms. Preclinical studies provide implications for the development of novel treatments, impacting the development of new drugs in clinical respects.