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Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model
S Roy1, R G Charboneau, R A Barke
1Department of Pharmacology, Veterans Administration Medical Center and University of Minnesota, Minneapolis 55417, USA. royxx002@gold.tc.umn.edu
Abstract:
Emergent or elective surgical procedures may be complicated by sepsis, resulting in critical illness that can lead to organ failure and death. The opioid drug, morphine is widely used to alleviate pain in post-surgical patients; however, it is well documented that chronic treatment of mice with morphine affects the proliferation, differentiation and function of immune cells. Thus, morphine might be expected to exacerbate the effects of sepsis, which also compromises the immune system. To test this notion, we investigated the effect on several immune functions of a clinical dose of morphine (4 mg/kg) superimposed upon a lipopolysaccharide (LPS)-induced infection model. Our results show that this relatively low dose of morphine, though generally having no effects on immune parameters by itself, significantly augmented LPS responses. A clinical dose of morphine (4 mg/kg body weight) superimposed upon an animal model of sepsis resulted in a significant increase in mortality at 48 h. In the absence of the drug, most septic animals died after 96 h. Phenotypic responses such as, decreased thymic cellularity, compromised mitogenic response and inhibition of IL-2 synthesis that are evident at 48-72 h after LPS injection appear as early as 24 h in animals that receive morphine in addition to LPS. In addition, our results show that in T cells there is a shift from TH1 type cytokine elaboration to a TH2 type cytokine elaboration in animals that receive both LPS and morphine.
Insights
Morphine, used for surgical pain, worsens sepsis outcomes in mice. This common painkiller significantly increased mortality and immune dysfunction in a sepsis model, highlighting potential risks in surgical patients.
Area of Science:
- Immunology
- Pharmacology
- Critical Care Medicine
Background:
- Sepsis is a life-threatening complication of surgery, often leading to organ failure.
- Morphine is a common postsurgical analgesic, but it can impair immune cell function.
- The combined effects of morphine and sepsis on the immune system are not fully understood.
Purpose of the Study:
- To investigate how a clinical dose of morphine affects immune responses during sepsis.
- To determine if morphine exacerbates the severity of a lipopolysaccharide (LPS)-induced sepsis model.
Main Methods:
- Mice were administered a clinical dose of morphine (4 mg/kg) alongside an LPS-induced sepsis model.
- Immune cell proliferation, cytokine production (IL-2), thymic cellularity, and mortality rates were assessed.
- T helper cell cytokine profiles (TH1 vs. TH2) were analyzed.
Main Results:
- Morphine significantly increased mortality in septic mice, with deaths occurring earlier (48 h vs. 96 h).
- Immune dysfunctions, including decreased thymic cellularity and impaired mitogenic responses, appeared earlier (24 h) with morphine co-administration.
- A shift from TH1 to TH2 cytokine profiles was observed in T cells from mice receiving both LPS and morphine.
Conclusions:
- A clinical dose of morphine can significantly worsen sepsis outcomes and immune compromise.
- Morphine administration may accelerate sepsis-induced immune dysfunction and increase mortality.
- Findings suggest caution when using morphine in surgical patients at risk for or experiencing sepsis.