Administration of opioid drugs such as morphine and heroin elicits pronounced effects on the immune system, including decreases in natural killer (NK) cell activity and lymphocyte proliferative responses. Despite a wealth of data indicating that opioids induce such immune alterations by acting through μ-opioid receptors in the brain, there is little known about how opioids interact with neurotransmitter systems to modulate specific immune parameters. The present investigations address how opioid interactions with dopamine transmission in the nucleus accumbens translate into peripheral immune alterations. The experiments presented in Chapter 2 revealed that pharmacological blockade of dopamine D₁ receptors in the nucleus accumbens shell abolished the suppressive effects of both morphine and heroin on the ability of splenic NK cells to lyse tumor cell targets. In contrast, selective stimulation of dopamine D₁ receptors in the nucleus accumbens shell produced reductions in splenic NK cell activity comparable to opioid administration. Additionally, antagonism of D₁ receptors in the nucleus accumbens shell completely prevented heroin’s inhibitory effects on in vivo iNOS expression in spleen, liver, and lung tissues. Chapter 3 showed that these dopamine-dependent immunomodulatory effects are mediated peripherally via the sympathetic peptide transmitter NPY. Administration of a selective NPY Y₁ receptor antagonist blocked opioid-induced decreases of NK activity and iNOS expression, but did not reverse the suppression of dopamine-independent effects on lymphocyte proliferative responses. Chapter 4 showed that similar dopamine and NPY receptor mechanisms underlie the conditioned immunomodulatory effects of opioids. Rats received conditioning sessions during which an injection of morphine was paired with a distinctive environment that served as the conditioned stimulus (CS). Administration of a either a D₁ antagonist or a Y₁ antagonist prior to CS re-exposure fully blocked the conditioned suppression of NK cell activity. Collectively these findings suggest that opioid-induced increases in dopamine release in the nucleus accumbens shell inhibit splenic NK activity and iNOS production by facilitating the NPY release from sympathetic nerves. Additionally, the findings suggest that conditioned and unconditioned immunomodulatory effects of opioids involve similar receptor mechanisms.