Opioid-induced microglia reactivity modulates opioid reward, analgesia, and behavior

Jacob M. Green, Mark H. Sundman, Ying hui Chou

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations


Opioid-induced microglia reactivity affects opioid reward and analgesic processes in ways that may contribute to the neurocognitive impairment observed in opioid addicted individuals. Opioids elicit microglia reactivity through the actions of opioid metabolites at TLR4 receptors, that are located primarily on microglia but are also present on astrocytes. Specifically, the M3G metabolite, which has no affinity for opioid receptors, exerts off-target effects on TLR4 receptors that can trigger downstream immunologic consequences. This off-target microglial reactivity, and the subsequent increase in microglial release of TNFα, IL-1β, and BDNF, have been suggested to modulate both opioid-induced reward and opioid-induced analgesia. Despite occurring independently of each other, these neuro-immune effects could converge and result in overactivation of the insula. This would produce an imbalance between the “impulsive system” and the “executive system”, such that the impulsive system's influence over behavior becomes dominant. This state, derived from changes in microglial reactivity, could contribute to impairment in a range of neurocognitive domains that are intricately involved in addiction and lead to increases in addiction-related behaviors.

Original languageEnglish (US)
Article number104544
JournalNeuroscience and Biobehavioral Reviews
StatePublished - Apr 2022


  • Analgesia
  • BDNF
  • Cognitive impairment
  • Hyperalgesia
  • IL-1β
  • Microglia reactivity
  • Neuroinflammation
  • Opioids
  • Reward
  • TNFα

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience


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