Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal

Neuron. 2007 Feb 15;53(4):577-89. doi: 10.1016/j.neuron.2007.01.022.


Escape from the extremely stressful opiate withdrawal syndrome may motivate opiate seeking and taking. The corticotropin-releasing factor receptor-1 (CRF1) pathway mediates behavioral and endocrine responses to stress. Here, we report that genetic inactivation (CRF1-/-) as well as pharmacological antagonism of the CRF/CRF1 receptor pathway increased and prolonged the somatic expression of opiate withdrawal. Opiate-withdrawn CRF1-/- mice also showed aberrant CRF and dynorphin expression in the paraventricular nucleus of the hypothalamus (PVN) and the striatum, indicating profound impairments in stress-responsive brain circuitry. Intake of nonstressful amounts of corticosterone effectively reduced the exaggerated somatic reactions of CRF1-/- mice to opiate withdrawal. Exogenous corticosterone also restored "wild-type-like" patterns of CRF and dynorphin gene expression in the PVN and the striatum of opiate-withdrawn CRF1-/- mice, respectively. The present findings unravel a key role for the hypothalamus-pituitary-adrenal (HPA) system and brain extra-hypothalamic CRF/CRF1 receptor circuitry in somatic, molecular, and endocrine alterations induced by opiate withdrawal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Corticosterone / blood
  • Corticosterone / therapeutic use
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism
  • Disease Models, Animal
  • Dynorphins / genetics
  • Dynorphins / metabolism
  • Female
  • Mice
  • Mice, Knockout
  • Morphine / adverse effects*
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Receptors, Corticotropin-Releasing Hormone / deficiency
  • Receptors, Corticotropin-Releasing Hormone / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stress, Psychological / complications*
  • Substance Withdrawal Syndrome / blood
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / genetics
  • Substance Withdrawal Syndrome / physiopathology*
  • Time Factors


  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Dynorphins
  • Morphine
  • Corticotropin-Releasing Hormone
  • Corticosterone