AIMS: Recent studies suggest important roles for glial cells (astrocytes and microglia) in the development, differentiation and survival of neurons in the brain. Neurotoxins released from microglial cells (the main immune cells in the brain) in response to adverse neuroimmune reactions may cause the death of neurons and are believed to be the major cause of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The purpose of this project was to evaluate the roles of opioid receptors in the interactions between glia and neurons. Our major efforts have focused on the influences of an opioid receptor antagonist, naloxone, on the release of proinflammatory cytokines, production of reactive nitrogen free radicals, and neurotoxicities induced by endotoxins or neurotoxins. In order to achieve these goals, we have developed a mixed neuronal/glial cell co-culture system as a model to examine the roles of microglia and astroglia in the survival of neurons in response to various insults. ACCOMPLISHMENTS: One of the most interesting findings from this series of studies was the inhibitory influences of naloxone on lipopolysaccharide (LPS) -induced effects. Pharmacological concentrations of naloxone (10-6 M) were found to inhibit the LPS-induced release of proinflammatory cytokines, such as TNFa or IL-1, and the production of nitric oxide in mixed glial cell cultures. Immunocytochemical studies revealed that the inhibitory effect of naloxone results from the reduction in LPS- induced activation of microglia. Using mixed neuron/glia cultures as a model for neurotoxicity, we have recently observed that naloxone reduced LPS-induced neuronal cell death. Nor- binaltrophimine, a selective kappa opioid receptor antagonist, also reduced the LPS-induced neurotoxicity suggesting that the kappa opioid receptor subtype is involved in the activation of microglia. To determine whether the inhibitory effect of naloxone can be observed in vivo, we have injected LPS into the substantia nigra of the rat brain to destroy the dopamine- containing neurons. Infusion of naloxone greatly reduced the LPS-induced neuronal death. These findings suggest the possible involvement of opioid receptors in the activation of microglia by endotoxins and also point to the possibility that naloxone or related kappa opioid receptor antagonists can be considered as candidates for the treatment of inflammation-related neurodegenerative diseases.
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