The magnocellular neuroendocrine system is comprised of neurons in the hypothalamus that synthesize oxytocin or vasopressin and release these peptides both from their dendrites within the supraoptic nucleus (SON) of the central nervous system and from their axon terminals in the neural lobe in response to physiological stimuli. Vasopressin is important in the regulation of blood pressure and fluid balance whereas oxytocin facilitates parturition and stimulates milk let-down to nursing infants during lactation. Recently, interleukin-1ß (IL-1ß) a proinflammatory peptide of the immune system, was identified in small granules within oxytocin and vasopressin neurons. All three peptides co-deplete from pituitary stores in response to salt-loading and during lactation when there is chronic activation of the magnocellular system. Other biochemical mediators of inflammation are also present throughout this neuroendocrine system. Specifically, nitric oxide (NO), a potentially toxic, highly diffusible gas is formed in magnocellular neurons by neuronal NO synthase, whereas prostaglandins also have a role in modulating release of oxytocin and vasopressin into the circulation. Research is focused on understanding the neurobiology of IL-1ß and its interaction with NO and prostaglandins in regulating the central (dendritic) and peripheral (axonic) release of oxytocin and vasopressin. The long-range goal is to identify and develop new targets for anti-inflammatory drugs. Our studies also have the potential to discover new therapies for treatment of neurodegenerative diseases and injury to the nervous system, since magnocellular neurons in the adult nervous system undergo morphological restructuring (i.e. plasticity) involving the formation of new synapses and neuronal contacts during chronic stimulation. Currently, micro-dialysis of the SON area of conscious rats is being used to monitor dendritic release of IL-1ß, oxytocin and vasopressin . These peptides are quantified in the same ultra-low volume of dialysates by immuno-affinity capillary electrophoresis with laser-induced fluorescence detection. Classic neuroendocrine studies using pharmacological tools, such as enzyme inhibitors and receptor antagonists microdialyzed directly into the SON, are also used to define the neuromodulatory roles of potentially destructive proinflammatory mediators (IL-1ß, NO and prostaglandins) as physiological regulators of the magnocellular system. Changes in Fos expression will functionally map afferent neural pathways innervating magnocellular neurons that are responsive to IL-1ß and its receptor antagonist. Radioimmunoassay and elisas are also being used to measure levels of IL-1ß, oxytocin, and vasopressin in plasma and extracts of the SON and neural lobe during salt-loading and lactation.