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Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice

Juan-Antonio García-Carmona1, Elena Martínez-Laorden1, María-Victoria Milanés1

  • 1Department of Pharmacology, School of Medicine, University of Murcia, Spain.

Toxicology and Applied Pharmacology
|January 14, 2015
PubMed

Insights

Stress from opioid withdrawal activates brain pathways influencing heart function. Blocking the CRF1 receptor (CRF1R) significantly reduced these stress responses, suggesting a link between CRF/CRF1R signaling and cardiovascular disease in opioid addiction.

Area of Science:

  • Neuroscience
  • Cardiovascular Science
  • Pharmacology

Background:

  • Stress is a known risk factor for cardiovascular disease, but the specific brain mechanisms are not fully understood.
  • Opioid withdrawal is a significant stressor with potential cardiovascular implications.
  • The role of the corticotropin-releasing factor type 1 receptor (CRF1R) in mediating stress-induced cardiovascular changes requires further elucidation.

Purpose of the Study:

  • To investigate the role of CRF1 receptor (CRF1R) in the cardiovascular and neural stress responses during naloxone-precipitated morphine withdrawal.
  • To examine the involvement of CRF1R in noradrenaline (NA) turnover and related signaling pathways in key brain regions and the heart.

Main Methods:

  • Experiments were conducted using genetically engineered mice lacking functional CRF1R (KO) and wild-type littermates.
  • Morphine withdrawal was induced by naloxone administration after escalating morphine doses.
  • Key markers including noradrenaline (NA) turnover, c-Fos expression, protein kinase A (PKA), and tyrosine hydroxylase (TH) phosphorylation were assessed using HPLC, immunohistochemistry, and immunoblotting.

Main Results:

  • Morphine withdrawal increased NA turnover and TH neuron activity in the paraventricular nucleus (PVN) and ventrolateral medulla (VLM) in wild-type mice.
  • Withdrawal also elevated NA turnover, TH phosphorylation, and PKA levels in the heart of wild-type mice.
  • These withdrawal-induced changes in the brain and heart were significantly attenuated in CRF1R KO mice.

Conclusions:

  • CRF/CRF1R activation plays a crucial role in the adaptive cardiovascular and neural responses to opioid withdrawal.
  • CRF1R signaling influences cardiac sympathetic function through brain pathways.
  • These findings suggest that CRF/CRF1R pathways may contribute to cardiovascular complications associated with opioid addiction.
Keywords:
CRF1R knockout miceHeartHypothalamic paraventricular nucleusNaloxone-precipitated morphine withdrawalVentrolateral medulla

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