Dorsal horn neurocircuitry, once thought to be rigidly structured, has been shown to change in response to various peripheral manipulations. This plasticity is observed in the animal model of experimental peripheral neuropathy (EPN). This EPN model exhibits the classic symptoms seen in human peripheral neuropathies including hyperalgesia, allodynia, abnormalities in skin temperature, abnormalities in nail growth and possibly spontaneous pain. In addition to behavioral manifestations, the model results in changes in the dorsal horn, including increases in dynorphin (DYN), decreases in primary afferent transmitters (i.e., calcitonin gene-related peptide, CGRP), and the appearance of """"""""dark neurons"""""""" (dead and dying cells due to transynaptic degeneration). One of the most intriguing phenomenae is the increase in the number of cells expressing DYN. This peptide is unique in that several different manipulations result in its up-regulation in the dorsal horn. It is hypothesized that increased primary afferent activity is responsible for this up-regulation. Nothing is known about DYN neurocircuitry in the spinal cord. Hence, this up-regulation could be the result of direct primary afferent input or the result of disinhibition [i.e., decrease in gamma-amino butyric acid (GABA input]. In the present proposal, the frequency of interactions of CGRP-DYN, CGRP-GABA and DYN-GABA profiles will be investigated in the dorsal horn of normal and EPN monkeys. The peripheral neuropathy is induced by tying 4 slightly constricting sutures around the sciatic nerve. Within 2-10 days, behaviors are manifested which resemble the symptoms observed in human peripheral neuropathies. Behavioral testing of sensory thresholds accompanied by daily observation will confirm the presence and degree of severity of the neuropathy. Behavioral changes will be correlated with changes in CGRP, DYN and GABA neurocircuitry, analyzed at the light and electron microscopic levels. The long term goal of these studies is to gain an understanding of the neural mechanisms underlying DYN-regulation, using the EPN to induce this phenomena. It is anticipated that knowledge of DYN neurocircuitry may lead to the development of drugs which can either directly or indirectly target the spinal DYN system, leading to better and/or more specific analgesic agents. Furthermore, understanding the plasticity of neurocircuitry in peripheral neuropathies could lead to improved clinical treatment of this common neural disorder.
