MUCOSAL DEFENSE MECHANISMS IN SUBSTANCE ABUSE

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DESCRIPTION: (Applicant's Abstract) The acquired immunodeficiency syndrome is associated with a high incidence of intestinal disease resulting from primary human immunodeficiency virus (HIV) infections and secondary opportunistic infections of the intestinal mucosa. The mucosa protects the immense surface area encompassed by the intestine from invasion by pathogenic microorganisms and controls proliferation of resident gut microflora. These protective mechanisms include: (1) active water and ion secretion which dilutes and purges luminal pathogens; (2) the integrity of the epithelium to macromolecular and microbial penetration; and (3) local immune reactions to luminal antigens mediated by gut-associated lymphoid tissue. Morphine and other opioids suppress immunity and decrease disease resistance in animals and humans. However, their ability to modify intestinal host defense mechanisms is not well defined. We hypothesize that opioids suppress mucosal defense through interactions with mucosal and submucosal opioid receptors (ORs). Thus, drugs of this class could reduce host resistance to intestinal infections and promote seeding of enteric microorganisms to extra-intestinal sites. Using the small intestine of normal and morphine-dependent pigs as an experimental model, we will test this hypothesis through the following specific aims: (1) localize ORs in the intestinal mucosa and submucosa through analyses of specific opioid binding sites and identification of OR mRNAs in epithelial cells and submucosal neurons, and localization of OR-like immunoreactivity on cholinergic and peptidergic submucosal neurons using novel anti-OR antisera; (2) characterize ORs which suppress mucosal secretion through electrophysiological measurements of transcellular ion fluxes across sheets of ileal mucosa-submucosa, elucidation of neurochemical circuits involved in opioid actions, and determination of opioid suppression of mucosal secretion induced by inflammatory mediators and HIV envelope proteins; (3) define opioid effects on epithelial barrier function through electrophysiological determinations of tissue conductance and quantitation of transepithelial microparticle penetration; and (4) assess the influence of morphine tolerance on opioid-induced changes in mucosal secretion, barrier function and the acquisition of local immune responses to specific antigens. This study will provide new and clinically important data on opioid actions in first-line mucosal defense against pathogens, such as HIV, that infect or emanate from the intestinal tract.