In late life, otherwise normal individuals may be afflicted by an age-related peripheral neuropathy that involves small caliber nerve fibers, producing complex, crippling, painful syndromes. Through systematic application of specialized clinical methods (quantitative psychophysical sensory tests, thermography, and autonomic testing), we have identified two distinct subsyndromes: a) patients with """"""""burning"""""""" feet and legs which are objectively hot and improve with cooling, and, b) reverse image patients with """"""""burning"""""""" limbs which are objectively cold and worsen with cooling (Ochoa, 1989b). In patients with overt peripheral neuropathy expressing comparable sensory phenomena, preliminary investigation combining specialized clinical tests with experimental selective nerve fiber blocks, intraneural microrecordings, and quantitative morphometry of biopsied nerves, indicates that the """"""""hot"""""""" syndrome results from sensitization of unmyelinated C nociceptor (pain) sensory units (Cline, Ochoa & Torebjork, 1989). This """"""""hot"""""""" syndrome as delineated in patients is completely replicated during experimental neurogenic inflammation elicited by acute capsaicin application (Culp, Ochoa, Cline & Dotson, 1989). The """"""""cold"""""""" syndrome might have related pathophysiology or may reflect a classic central release phenomenon of C nociceptor input due to damage of cold-specific afferents (Yamitsky & Ochoa, 1989a). The primary goals of the research proposed here are to further characterize the clinical phenomenology in painful late life neuropathy and to test a series of specific hypotheses concerning the pathophysiological basis for the painful syndromes. Experiments are designed to test possible existence of a) sensitized nociceptors, b) antidromic neurogenic inflammation, c) various patterns of vasoconstriction related to sympathetic efferent activity or denervation, and, d) central disinhibition of primary pain input due to release mechanisms. Local nociceptor sensitization and desensitization will be produced by means of specific neurotoxins, such as capsaicin, to test pathophysiology of the pains and vascular phenomena, and to predict potential therapeutic outcome (Simone, et al, 1989). An ultimate goal is to actually treat painful syndromes emanating from activity in C nociceptor units which remain functionally connected to cutaneous receptors. This will be attempted through abolition of either primarily exaggerated or centrally disinhibited sensory input from first order pain neurons by nociceptor desensitization.
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