This project is investigating the role of CNS peptide-containing neurons in sensory processing. A model of chronic peripheral inflammation has been developed in order to understand the relationship between spinal cord opioid-containing neurons (enkephalin and dynorphin) and abnormal afferent input due to inflammatory processes. Spinal cord dynorphin neurons exhibit a three-fold increase in peptide content at the peak of inflammation; in contrast, little effect is seen for the enkephalin-containing neurons. In order to examine further the physiological implications of the dynorphin peptide increase we have measured the levels of the mRNAs coding for the dynorphin and enkephalin peptide precursor proteins. RNA blots were prepared from poly A+ enriched RNA isolated from rat dorsal spinal cord under control and inflammation conditions. The dynorphin mRNA was found to undergo a nine-fold increase after inflammation. This result has been reproduced twice. In contrast, the enkephalin mRNA is increased to a much smaller extent (50-100% over control). Preliminary time course results indicate that the dynorphin mRNA is increased as early as day two of inflammation. The changes in dynorphin peptides and mRNA parallel one another and also parallel the development of a marked hyperalgesio to both a thermal stimulus and a mechanical stimulus. These data suggest that there is a mild activation of spinal cord enkephalin neurons and a marked activation of spinal cord dynorphin neurons since the synthesis of both message and peptide are increased. Thus, spinal dynorphin neurons may play a unique role in modulating inflammatory pain. The significance of these studies is that they provide a model in which to study the in vivo regulation of opioid neurons and a new framework from which to evaluate the role of multiple spinal opioid neurons in the control of chronic pain as encountered in arthritis, injury and possibly cancer. Further elucidation of the pivotal role of the spinal dynorphin system may provide a new avenue for the pharmacotherapy of the chronic pain state as well as insights into chronic opioid abuse and tolerance.
