Evidence for the Nucleus Accumbens as a Neural Substrate of Heroin-Induced Immune Alterations

Abstract

Administration of opioid drugs such as heroin produces several immunosuppressive effects, including decreases in natural killer (NK) cell activity, lymphocyte proliferative responses, and nitric oxide production. Interestingly, opioids have been shown to alter many immune parameters indirectly by modulating the immunoregulatory actions of the central nervous system. Recently, it has been demonstrated that morphine inhibits NK cell activity through a neural pathway that requires the activation of dopamine D 1 receptors in the nucleus accumbens shell. The present study examined whether the nucleus accumbens also mediates the effects of heroin, a more commonly abused opioid, on several parameters of immune status in Lewis rats. The results showed that bilateral administration of the dopamine D 1 receptor antagonist R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.015 and 0.15 g/side) into the nucleus accumbens shell blocked decreases in splenic NK activity produced by heroin (3 mg/kg s.c.) but did not attenuate the suppression of splenocyte proliferative responses to concanavalin-A or lipopolysaccharide (LPS). A subsequent experiment was performed to evaluate the effect of D 1 receptor antagonism on LPS-induced expression of inducible nitric-oxide synthase (iNOS) in vivo. These results showed that intra-accumbens SCH-23390 administration prevented heroin-induced reductions of iNOS mRNA expression in spleen, liver, and lung tissues and attenuated the suppression of nitric oxide levels in plasma. Collectively, these findings indicate that nucleus accumbens dopamine D 1 receptors are critically involved in heroin-induced immune alterations.Opioid drug use is associated with adverse health consequences. Heroin abusers display abnormalities in basic immune parameters and have high rates of viral, bacterial, and fungal infections (Louria et al., 1967;Govitrapong et al., 1998). Although the high incidence of infectious diseases among abusers is commonly attributed to increased pathogen exposure or insalubrious behaviors, opioids exert potent immunomodulatory effects that may further enhance infection susceptibility. Controlled studies in humans demonstrate that morphine produces immunosuppressive effects in healthy, nondrug-using subjects (Yeager et al., 1995), and clinical reports indicate that higher doses of opioid analgesics are associated with greater frequencies of infectious complications among burn victims and patients that underwent cardiac surgery (El Solh et al., 2006;Schwacha et al., 2006). Thus, the use of opioids, whether for therapeutic or recreational purposes, may directly influence resistance to infectious diseases.In animal models, morphine has been shown to suppress a variety of immune parameters, but the mechanisms underlying these effects are not fully understood Lockwood et al., 1994). Opioids modulate immunity in a highly complex manner by interacting with opioid receptors expressed by multiple cell types throughout the body. For exa...

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