In the course of studies investigating the effects of opioids on the immune system, we observed that implantation in mice of a 75-mg slow-release morphine pellet results in colonization of the livers, spleens, and peritoneal cavities with enteric organisms including Proteus mirabilis, Esherichia coli and enterococci 24 to 48 hr later. Further, mice given morphine were sensitized to a sublethal dose of lipopolysaccharide (endotoxin). Simultaneous implantation of a naltrexone pellet with the morphine pellet blocked colonization and endotoxin-mediated lethality. Our results suggest that morphine potentiates sepsis, a hypothesis with far-reaching implications in medical management of post-operative pain. Sepsis is a major health problem in the United States, with a minimum of 100,000 cases per year. Many of these cases occur in hospitalized patients that are post surgical. To extend our observations, we propose to l) carry out more extensive pharmacologic studies of this phenomenon including kinetics of onset of translocation of bacteria from the gastrointestinal tract; effect of dose, route, and mode of opioid delivery on induction of sepsis; comparison of effects of morphine with other opioids; and investigation of the opioid receptor type which mediates this phenomenon; 2) examine the effect of morphine and other opioids on capacity of two oral pathogens, Salmonella typhimurium and Listeria monocytogenes, and their attenuated variants, to translocate out of the gastrointestinal tract; 3) more thoroughly characterize the septic state by investigating the cytokine response and induction of inducible nitric oxide synthase (iNOS) in mesenteric lymph nodes, spleen, liver, blood, and peritoneal cavity of morphine or other opioid-treated mice using a quantitative, competitive RT-PCR technique; and 4) examine the effect of morphine or other opioids on immune responses and cellular composition in the gut-associated lymphoid tissue, including expression of cytokines and iNOS. This project deals with a major health problem and promises to cast significant insight into sepsis and the potential role of opioid receptors in this pathological state. It relates to events associated with both the therapeutic and non-therapeutic use of morphine and other opioid drugs.
Showing the most recent 10 out of 11 publications
