This proposal aims to determine the role of opioid agonists on chemokine receptor systems in neuronal cells, both at the receptor level and the subsequent signaling pathways associated with each in the context of HIV associated dementia. Recently, it has been postulated that opiate abuse promotes HIV-1 infection and disease progression including progression to NeuroAIDS. Indeed, recent studies indicate a direct interaction of opioids and their receptors with the HIV co-receptors CXCR4 and CCR5 on immune cells. This interaction is distinct from the general immunosuppressive actions of opioids. Our hypothesis is that mu-opioid agonists modulate CXCR4 chemokine receptor expression and/or activation and thus may alter the chemokine-induced cell signaling events, which play a role in neuronal survival. Indeed, our preliminary data indicate that mu-opioid receptor agonists can regulate CXCR4-dependent survival pathways in neurons. Therefore, SPECIFIC AIM 1 will evaluate whether mu-opioid agonists regulate A.) CXCR4 receptor expression or activation, and B.) the production of chemokines. In addition, SPECIFIC AIM 2 will evaluate the role of mu-opioid agonists on neuronal cell death by the HIV envelope protein gp120, as well as on the downstream signaling pathways activated by gp120. Experiments will be conducted predominantly in primary cultures of rat cortical neurons using the bilaminar cell culture system, which provides an excellent model to study a pure population of neurons in the presence or absence of non- neuronal cells. The data will provide insight into the interaction of the two distinct receptor systems and allow for a better understanding of the increased progression of HAD in opioid users.