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Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing

Ronald McGregor1,2,3, Ming-Fung Wu1,2,3, Thomas C Thannickal1,2

  • 1Neuropsychiatric Institute and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.

Nature. Mental Health
|February 24, 2025
PubMed

Insights

Opioid use disorder impacts hypocretin (Hcrt) neurons. Blocking Hcrt receptors with suvorexant may reduce opioid addiction potential while preserving pain relief.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Opioid use disorder (OUD) is a significant public health issue.
  • Chronic opioid administration alters hypocretin (Hcrt, also known as orexin) neuron function and brain circuitry.
  • Hcrt neurons play a role in reward and arousal systems, implicated in addiction.

Purpose of the Study:

  • To investigate the role of hypocretin signaling in opioid-induced neuroadaptations and behaviors.
  • To determine if blocking hypocretin receptors can mitigate the negative consequences of chronic opioid exposure.
  • To assess the impact of combined opioid and hypocretin receptor antagonist treatment on analgesia and addiction potential.

Main Methods:

  • Utilized rodent models of chronic morphine administration.
  • Administered the dual Hcrt receptor antagonist suvorexant concurrently with morphine.
  • Assessed changes in Hcrt neuron number and size, Hcrt projections to the ventral tegmental area (VTA), VTA tyrosine hydroxylase (TH) levels, and microglial activation.
  • Evaluated morphine-induced anticipatory behaviors, opioid withdrawal symptoms, and analgesic effects.

Main Results:

  • Chronic morphine decreased Hcrt neuron size and increased their number, while increasing Hcrt projections to the VTA and activating microglia.
  • Co-administration of suvorexant prevented these morphine-induced neurobiological changes.
  • Suvorexant treatment blocked morphine-associated anticipatory behaviors and reduced withdrawal symptoms.
  • Suvorexant did not attenuate the analgesic effects of morphine.

Conclusions:

  • Hypocretin signaling is critically involved in the neuroadaptations underlying opioid use disorder.
  • Blocking Hcrt receptors with suvorexant can prevent key neurobiological changes and behavioral aspects of opioid addiction.
  • Combined opioid and suvorexant administration offers a potential strategy to reduce the addiction liability of opioids for pain management without compromising analgesia.

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