Numerous studies have contributed significantly to our understanding of nociception-related circuitry in the rostroventral medulla (RVM). Work supported by this award has characterized facilitation and inhibition of spinal sensory transmission from the RVM that involves distinct, independent systems likely associated with neurons in RVM that are physiologically and functionally differentiated. Electrophysiololgical experiments have identified cells in RVM that differ based on response to noxious heating of the tail (in vivo) or effect of a mu opioid agonist (in vitro). Neither model of RVM circuitry arising from these studies is fully explanatory of the descending effects produced from RVM. This proposal describes experiments to more fully characterize responses of cells in RVM to non-opioid agonists. Specific Aim 1 will use whole cell patch clamp methods to record cells in vitro in an RVM slice preparation. Because cholecystokinin (CCK), neurotensin, glutamate and GABA play important roles in RMV-produced modulation of nociception, we will examine their effects on cell currents and synaptic transmission in RVM. The axonal projections of recorded cells in RVM will be known by content of retrograde tracer and RVM slices will be fixed and processed after recordings for determination of glutamic acid decarboxylase, tryptophan hydroxylase, enkephalin and/or CCK content. Despite evidence that the RVM plays a role in hyperalgesia, no information is available as to how the electrophysiologic and pharmacological character of RVM cells changes as a consequence of persistent peripheral tissue insult. Specific Aim 2 will reproduce experiments in specific aim 1, but RVM slices in these experiments will be taken from animals with persistent peripheral insult: complete Freund's adjuvant inflammation of a hindpaw, spinal nerve ligation (Chung model), or trinitobenzenesulfonic acid produced colon inflammation. We hypothesize that changes in the electrophysiologic properties and pharmacologic modulation of currents and/or synaptic transmission will be apparent in RVM cells after persistent peripheral insult consistent with alterations in excitability of RVM cells. The working hypothesis guiding these studies is that differences exist between cells in RVM that have yet to be determined. Better appreciation of these differences will enhance our understanding of the contributions these cells make to nociceptive processing, including their role in mechanisms of hyperalgesia.