Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence

Neuropsychopharmacology. 2013 Sep;38(10):1833-43. doi: 10.1038/npp.2013.117. Epub 2013 May 10.


Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Adrenergic Neurons / drug effects
  • Adrenergic Neurons / metabolism*
  • Animals
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism*
  • Locus Coeruleus / physiopathology
  • Male
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Opioid-Related Disorders / complications
  • Opioid-Related Disorders / metabolism
  • Opioid-Related Disorders / pathology
  • Opioid-Related Disorders / physiopathology*
  • Opioid-Related Disorders / psychology
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism*
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology
  • Substance Withdrawal Syndrome / psychology


  • Narcotic Antagonists
  • Oprm1 protein, rat
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Opioid, mu
  • Naloxone
  • CRF receptor type 1