Proinflammatory mediators in the brain are associated with a constellation of adaptive behaviors known as sickness behaviors. Although many studies have confirmed peripheral immunosuppressive effects of opiates, none have demonstrated effects of heroin or any other opiate on immune responses within the central nervous system. The following experiments examined the effects of heroin on brain proinflammatory mediators alone and during an immune challenge, and the effects that heroin has on sickness behaviors and proinflammatory mediators in associated brain regions.

Experiments in Chapter 2 established that heroin produces a reliable, short-term hyperthermia that is not reversed by pre-treatment of indomethacin, nor does it correlate with increased proinflammatory mediators in the hypothalamus, the area of the brain most associated with temperature changes. However, we did show that in the presence of an immune challenge (lipopolysaccharide, LPS), heroin appeared to have a suppressive effect on some proinflammatory mediators 90 minutes after treatment.

In Chapter 3, we further investigated these findings and examined both LPS-induced fever response and increased proinflammatory mediators in the hypothalamus, and determined that heroin has a suppressive effect on all proinflammatory mediators measured. In addition to the proinflammatory mediator suppression, heroin also attenuated fever production induced by LPS.

In Chapter 4, we examined the effects of heroin on LPS-induced proinflammatory mediators in the hippocampus, a region associated with behavioral depression. As in the hypothalamus, the hippocampus exhibited suppressed proinflammatory mediators when heroin treatment occurred concurrently with LPS treatment, although the hippocampus selectively showed these effects in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Additionally, heroin treatment diminished behavioral depression induced by LPS.

Taken together, these studies indicated that although heroin produced hyperthermia, heroin treatment does not acutely elevate proinflammatory mediators in the brain (Chapter 2), and when it is given in the presence of LPS, heroin has an immunosuppressive effect on both production of proinflammatory mediators and sickness behaviors (Chapters 3 and 4). Overall, these experiments demonstrate that heroin suppresses immune responses in the brain that are normally key parts of the process of producing adaptive sickness behaviors.