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Hypocretin/Orexin Interactions with Norepinephrine Contribute to the Opiate Withdrawal Syndrome

Ronald McGregor1,2, Ming-Fung Wu3,2, Brent Holmes2,4

  • 1Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California 90095 icelos3@gmail.com.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|December 2, 2021
PubMed

Insights

Chronic morphine exposure increases hypocretin/orexin (Hcrt) innervation in the locus coeruleus, impacting opioid withdrawal. This Hcrt system manipulation may offer new avenues for treating opioid addiction.

Area of Science:

  • Neuroscience
  • Addiction Research
  • Neuropharmacology

Background:

  • Previous studies indicated increased hypocretin/orexin (Hcrt)-producing neurons in human heroin addicts and morphine-exposed mice.
  • The role of Hcrt system changes in opioid withdrawal targets, like the locus coeruleus (LC), remained unclear.

Purpose of the Study:

  • To investigate the impact of increased Hcrt neuron number on Hcrt innervation in opioid withdrawal-related brain regions.
  • To determine the relationship between Hcrt innervation and tyrosine hydroxylase (TH) levels in the LC during morphine withdrawal.

Main Methods:

  • Immunohistochemistry
  • Biochemical assays
  • Imaging techniques
  • Behavioral analysis

Main Results:

  • Morphine administration significantly increased Hcrt innervation and tyrosine hydroxylase (TH) levels in the locus coeruleus (LC) without altering norepinephrine neuron numbers.
  • The observed increase in TH levels in the LC was dependent on Hcrt innervation.
  • The A1/A2 medullary regions were not affected by morphine treatment.
  • Eliminating Hcrt neurons prevented the TH increase in the LC and reduced opioid withdrawal symptoms.

Conclusions:

  • Hypothalamic Hcrt innervation of the LC is significantly upregulated by chronic morphine exposure.
  • This Hcrt system modulation plays a crucial role in the neurobiological adaptations underlying opioid addiction and withdrawal.
  • Targeting the Hcrt system presents a potential therapeutic strategy for opioid addiction and withdrawal management.
Keywords:
addictionanatomyhypocretinlocus coeruleusopioidswithdrawal

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