This project concerns the role of CNS peptide-containing neurons in sensory processes especially as they relate to pain and its control. A model of peripheral inflammation has been developed to investigate the relationship between spinal cord opioid- containing neurons (enkephalin and dynorphin) and abnormal primary afferent input. Alterations in opioid peptide biosynthesis are assessed by peptide and mRNA measurements and localization of the relevant neurons with immunocytochemical and in situ hybridization techniques. In our standard adjuvant-induced inflammation model examination of the time course of mRNA change disclosed that dynorphin mRNA undergoes a rapid increase (within 24 hours) and reaches a peak by 2 days whereas the peptide elevation is significant by 2-3 days and reaches a peak at 5 days. In contrast, enkephalin mRNA is only increased by about 60% during this period and the enkephalin peptide level is unchanged. These neurochemical changes are common to several other types of inflammation which we have tested (phorbol ester, yeast and carrageenan). Two groups of dynorphin-containing neurons have been identified by immunocytochemical and in situ hybridization methods. With both methodologies the up-regulation delineates a new neural circuit which we believe may be responsible for modulating pain at the spinal level. These data indicate that, in spinal cord, dynorphin is the major peptide system affected at all time points during the inflammation and that those neurons may play a unique role in modulating inflammatory pain. The significance of these studies is that they reveal how (and which) opioid neurons are coordinated in response to inflammatory pain and possibly pain associated with arthritis and cancer. Further eludication of the pivotal role of the spinal dynorphin system may provide a new avenue for the pharmacotherapy of pain and provide insights into chronic opioid abuse and tolerance.
