There is a body of evidence implicating the neurons of the rostral ventral medulla (RVM) in modulation of pain and, particularly, in mediating the analgesic effects of systemically administered opiate drugs such as morphine. Endogenous opioid peptide-containing neurons and terminals are present not only within RVM but are also present in other CNS sites that project to and receive projections from the RVM. In addition to enkephalin, there is evidence that serotonin, noradrenalin and other putative neurotransmitters are present in nerve terminals in RVM. Our goal is to elucidate the internal circuitry and function of RVM, particularly the role of opioid peptides. The strategy is to define RVM neuron cell classes on the basis of their receptive field and relationship of their discharge to nocifensive behavior. We will then map the location of each class and determine whether cells of that class project to the spinal cord. The effect on each class of either systemically injected or iontophoresed opiates will then be studied. Using intracellular marking of single RVM cells and double-labelling we plan to determine whether particular physiologically defined classes of cell contain particular transmitters or receive input from cells containing particular transmitters. We will use cross-correlation analysis to study connectivity between simultaneously recorded pairs of cells in RVM. In addition to better understanding of pain-modulating networks in the CNS, these studies, by defining the roles of both opioid and non-opioid neurons may suggest new classes of centrally-acting analgesic drugs.