Heroin-induced alteration in immune status in models of Gram-negative and Gram-positive bacterial infection.

摘要

In spite of the major health issues surrounding heroin use, there have been few studies directly examining the impact of heroin on immune status. The present studies investigated heroin's impact on the expression of the key proinflammatory mediators inducible nitric oxide synthase (iNOS), interleukin-one beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha).; The experiments presented in Chapter 2 show that animals injected with the Gram-negative bacterial fragment lipopolysaccharide (LPS) in conjunction with heroin have a pronounced suppression of iNOS, IL-1beta, and TNF-alpha, and show an attenuated febrile response. In contrast, animals injected with heroin and the Gram-positive bacterial fragments lipoteichoic acid (LTA) and peptidoglycan (PG) show no significant immune alterations. These studies suggest that heroin may have differential effects on immune status dependent upon the type of bacterial challenge employed to stimulate the immune response.; The studies detailed in Chapter 3 examined the impact of self-administered versus passively infused heroin on 4 mediator expression. These investigations show that animals will self-administer sufficient amounts of heroin on a fixed-ratio one (FR1) schedule of reinforcement (i.e., each lever press results in one intravenous infusion of heroin) to cause significant reductions in LPS-induced proinflammatory mediator expression. Additionally, self-administering animals showed a trend toward greater reductions than their yoked partners who received simultaneous, but passive, infusions of heroin. Further studies showed that by increasing the response requirement to receive heroin infusions from FR1 to FR10, while greatly increasing the response behavior, did not differentially impact the expression of the proinflammatory mediators measured in self-administering and yoked heroin animals.; To investigate heroin's immunomodulatory effects in a clinically relevant model of live infection, Chapter 4 includes studies that assessed the effects of an acute heroin injection on proinflammatory mediator expression and bacterial dissemination in animals challenged with live group B streptococcus (GBS). The studies show that heroin suppresses GBS dissemination from the site of injection (peritoneum) that cannot be explained by decreases in proinflammatory mediator expression. These findings suggest that heroin may play a 'protective' role in delaying Gram-positive bacterial dissemination from the site of infection, but the precise mechanism mediating this effect has not been determined.