Nucleus caudalis neurons that express the opioid peptide neurotransmitter genes preproenkephalin and preprodynorphin are prominently implicated in the modulation of dental and other orofacial pain by primary afferent inputs, descending brainstem systems, and even by opiate drugs. However, the details of these interactions and the differential roles that peptides derived from each of these genes might play in these processes remain obscure. This proposal will utilize recently-developed in situ hybridization techniques to quantitatively assess the relative levels of expression of these two genes in nucleus caudalis neurons. It will confirm the specific patterns of alterations in the neuronal expression of each of these genes that we have found after removal or stimulation of the trigeminal nerve in preliminary studies. These results provide intriguing evidence for opposite changes in expression of preproenkephalin and preprodynorphin in specific neuronal subpopulations in response to removal of primary afferents, and of differential cellular responses to stimulation of fibers of different diameters. Influences of stimulation of the descending painsuppressing pathways originating from the periaqueductal grey will also be evaluated. Finally, the impact of the opiate agonist and antagonist drugs that have been found in our laboratories to modulate expression of these genes in striatal neurons will be assessed in neurons of the nucleus caudalis. These changes in neuronal mRNA levels could indicate altered rates of release of peptides from neurons expressing each of the genes if the rates of translation, processing, intracellular transport and degradation and the size of peptide stores were stable in these settings. This information will enhance appreciation of the complex but potentially powerful impact of these stimuli on the function of the nucleus caudalis neurons that provide a crucial first level of modulation of dental and orofacial pain.
