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Opiate addicts have been shown to have a high susceptibility to bacterial infection. We investigated how treatment with morphine alters lipopolysaccharide (LPS)-induced inflammatory responses in the rat. Chronic morphine alone elevated serum endotoxin levels. Animals treated with morphine and LPS (250 microg/kg) developed hypothermia, decreased mean arterial pressure (MAP), increased plasma thrombin anti-thrombin III (TAT) complex, and approximately 67% of animals exhibited progressive intramicrovascular coagulation. Morphine also enhanced LPS-induced leukocyte-endothelial adhesion (LEA), suppressed leukocyte flux, and corticosterone production, and elevated interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 serum levels. Our study presents both the molecular and cellular mechanisms underlying the potentiated LPS-induced inflammation and accelerated progression to septic shock seen with chronic morphine exposure.

Vascular endothelial cells (VEC) provide an essential protective barrier between the vascular system and underlying tissues. Using VEC barrier models of human coronary artery cells and human and rat brain microvascular endothelial cells, we investigated the mechanism by which morphine affects lipopolysaccharide (LPS)-induced VEC permeability. We demonstrated that co-administration of morphine and LPS induced greater VEC apoptosis and permeability than morphine or LPS alone. The extent of induced apoptosis appeared to be cell-type dependent. Furthermore, RT-PCR analysis revealed that morphine and LPS up-regulated Fas expression. These data suggest potential crosstalk between the signaling pathways that mediate morphine- and LPS-triggered apoptosis in brain VEC.

Interleukin-1-beta (IL-1beta) can promote inflammation by up-regulating vascular adhesion molecules and inhibit inflammation by activating the hypothalamic-pituitary-adrenal (HPA) axis to produce anti-inflammatory glucocorticoids. In this study, chronic morphine was shown to suppress IL-1beta-induction of corticotropin releasing factor (CRF) mRNA and plasma corticosterone levels. Leukocyte-endothelial adhesion (LEA) in rat mesenteric venules increased during IL-1beta- and FMLP-induced inflammation. Chronic morphine potentiated the LEA response to either IL-1beta or FMLP alone, and greatly enhanced LEA in response to combined IL-1beta and FMLP. Thus, it appears that chronic morphine exposure may promote a potentially damaging inflammatory reaction by disrupting the balance between IL-1beta-mediated local inflammation and the anti-inflammatory effects of the HPA axis.