This project concerns the role of spinal cord peptide-containing neurons in sensory processing. A model of chronic peripheral inflammation has been developed in order to relate changes in the dynamic state of enkephalin, dynorphin (opioid) and cholecystokinin neurons to prolonged abnormal afferent input. A three-fold increase in dorsal spinal cord dynorphin content (dynorphin A 1-18 and 1-17) occurs by six days of inflammation and significant increases are observed as early as 3 days. The immunoreactivity materials have been identified by HPLC and gel chromatography in both control and treated conditions. Maintenance of the inflammation up to 14 days maintains the increase in dynorphin. The increase is specific to dorsal horn where sensory processing occurs, and is confined to spinal segments which subserve hindpaw sensation; no alteration of cervical cord dynorphin is observed. At the same time, no significant alteration in dorsal cord enkephalin (met5-enkephalin-arg6-gly7-leu8) or CCK content is observed. However, hybridization of the total dorsal cord RNA with a proenkephalin specific cDNA probe reveals a sharp increase in enkephalin mRNA content at 24 hours with return to near normal by three days. In periaqueductal grey a 40-70% increase in enkephalin content occurs by day of inflammation. No change occurred in dynorphin or CCK in this and several other brain regions. These data suggest on acute by transient activation of spinal enkephalin neurons and a delayed but sustained activation of spinal dynorphin neurons in response to chronic pain. Brain enkephalin pain pathways also respond to the chronic stimulus. The significance of these studies is that they provide a model in which to study the regulation of opioid neurons and a new framework from which to evaluate the role of multiple spinal opioid systems in control of chronic pain as encountered in arthritis and 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.
| Rabinowicz, Theodore; Petetot, Jean Macdonald-Comber; Khoury, Jane C et al. (2009) Neocortical maturation during adolescence: change in neuronal soma dimension. Brain Cogn 69:328-36 |
