There is a well-recognized intersection between drugs of abuse and AIDS or other states of compromised immune function, but the mechanisms behind this interaction are just beginning to be revealed. Cross-talk between opioids or cannabinoids and chemokines (small proteins produced by both microglia and neurons in the brain) occurs both in vitro and in vivo. For example, heterologous cross-desensitization, in terms of reduced chemotactic and antinociceptive activities, occurs between opioids and chemokines that are involved in HIV entry into cells. Our findings since the last competing renewal demonstrate unequivocally that the opioid, cannabinoid, and chemokine systems interact in both the immune system and the nervous system. Our results, with those from other laboratories, have led us to propose that the chemokine system in the brain is a major communication system between neurons, and between glia and neurons, thus joining neuropeptides and neurotransmitters subserving this function in normal and pathological states. It is the purpose of the proposed studies to document the nature of the interactions among these three classes of ligands and their receptors. Specifically, we propose to 1) explore the functional and biological consequences of injection of selected chemokines into various brain areas in terms of their altering the actions of drugs of abuse, including analgesia, thermoregulation, tolerance,and dependence;2) examine the reciprocal effect of opioids and cannabinoids on the activity of chemokines in the brain, and 3) assess neurophysiological effects of the chemokines alone and with opioids or cannabinoids in brain slices. The drugs chosen alter levels of HIV when added to human lymphoid, monocytic, or microglial cultures in vitro and interact with the chemokine receptors involved in HIV infection. The chemokines to be studied are ligands for HIV chemokine co-receptors. The implications for public health include altering treatment of pain associated with neuroinflammatory states, treatment of neuropathies associated with HIV, altering the ability of HIV to enter cells, altering actions of neurotransmitter/neuropeptide systems involved in the effects of drugs abused or used therapeutically, and potentially bringing new approaches to prevention and treatment of drug abuse and neurodegenerative diseases and AIDS through affecting the actions of chemokines and their receptors in the nervous system.