Morphine withdrawal sensitizes mice to lipopolysaccharide: elevated TNF-alpha and nitric oxide with decreased IL-12

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Updated: Aug 17, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

Pu Feng1, Joseph J Meissler, Martin W Adler

  • 1Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Journal of Neuroimmunology
|May 26, 2005
PubMed

Insights

Morphine withdrawal dramatically increases sepsis (LPS) lethality in mice. This heightened mortality is linked to elevated tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, suggesting TNF-alpha inhibition as a protective strategy.

Area of Science:

  • Immunology
  • Pharmacology
  • Toxicology

Background:

  • Opioid dependence is a significant public health issue.
  • Opioid withdrawal can trigger complex physiological changes.
  • Sepsis, often caused by bacterial lipopolysaccharide (LPS), is a life-threatening condition.

Purpose of the Study:

  • To investigate the impact of morphine withdrawal on susceptibility to lipopolysaccharide (LPS)-induced lethality.
  • To elucidate the immunological mechanisms underlying this heightened susceptibility.

Main Methods:

  • Morphine dependence was induced in mice using slow-release pellets over 96 hours.
  • Animals were withdrawn from morphine or placebo, followed by administration of LPS or saline.
  • Serum levels of TNF-alpha, nitric oxide, and IL-12 were measured.
  • The effect of anti-TNF-alpha antibody treatment was assessed.

Main Results:

  • Morphine-withdrawn mice challenged with LPS exhibited 100% mortality.
  • Control groups (placebo withdrawal + LPS, morphine withdrawal + saline) survived.
  • LPS-treated, morphine-withdrawn mice showed elevated serum TNF-alpha and nitric oxide, and reduced IL-12.
  • Anti-TNF-alpha antibody administration significantly protected morphine-withdrawn mice from LPS lethality.

Conclusions:

  • Morphine withdrawal sensitizes mice to LPS-induced lethality.
  • Elevated TNF-alpha production during morphine withdrawal is a key mediator of this sensitization.
  • Targeting TNF-alpha may offer a therapeutic approach to mitigate sepsis mortality in opioid-dependent individuals undergoing withdrawal.

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