Dorsal root ganglion (DRG) neurons are involved in the transmission of nociceptive information from peripheral tissues to the central nervous system. A class of these sense organs differ from all others in that they display a property called """"""""sensitization"""""""" wherein the response to successive noxious stimuli increases and the threshold is lowered - the opposite of """"""""adaptation"""""""". Recently several neuropeptides known as tachykinins (substance P, substance K, and neuromedin K) have been shown to be synthesized by mammalian DRG neurons. Recent data has strongly implicated these neuropeptides in the afferent transmission of nociceptive information and in the efferent regulation of inflammation and sensitization in peripheral tissues. In addition another powerful vasodilator, calcitonin gene related peptide (CGRP), has been shown to co- exist with substance P containing DRG neurons and appears to potentiate the nociceptive actions of substance P in the rat spinal cord. The hypothesis we will test in the present proposal is whether tachykinin and CGRP-containing DRG neurons change biochemically and pharmacologically in response to an inflammatory pain state, and if so, to what extent these changes are associated with the phenomena of sensitization. The model system we will use to investigate this will be a standard experimental arthritis in the rat which will serve as a simple, reproducible and humane animal model of a chronic pain syndrome of high incidence in man. The goal of the present proposal is clear; to understand how peripheral tachykinin and CGRP containing neurons are involved in the genesis of chronic pain and inflammation in arthritis and to determine the effectiveness of the 30 known putative tachykinin antagonists in ameliorating the pain or inflammation associated with the arthritic condition. We feel the proposed work is the most tangible, direct and quantitative approach for studying those factors which might activate nociceptors in ordinary innocuous joint movement; obviously a problem of practical importance.
Showing the most recent 10 out of 96 publications
