Abnormal neuronal mechanisms underlying chronic neuropathic pain and hyperalgesia will be explored in patients, making use of a novel array of rigorous neurophysiological techniques now available for human studies and in use in our laboratory. Results from the proposed experiments are expected to improve the scientific foundation for diagnosis and management of these patients, many of whom presently undergo ill conceived clinical investigation or receive ineffectual treatment. The experimental plan will test the following hypotheses: 1. Activity in abnormally sensitive (or ephaptically excited) primary nociceptors underlies spontaneous pain and hyperalgesia. 2. Activity in low-threshold myelinated mechanoreceptors excites abnormally sensitive spinal neurons to cause the spontaneous pain and hyperalgesia. 3. Sympathetic efferent activity, through excitation of low-threshold primary mechanoreceptors or sensitized nociceptors, triggers the abnormal mechanisms responsible for spontaneous pain and hyperalgesia. These scientifically based hypotheses are now amenable to direct testing in patients, eliminating the necessity of extrapolating results from animal research. Consenting patients, personally examined and preselected through our Neurosensory Unit, will undergo quantitative sensory testing and microneurography before and during introduction of controlled experimental variables intended to: a) selectively activate, naturally or electrically, subpopulations of primary sensory units; b) selectively block, mechanically or pharmacologically, subpopulations of primary afferent fibers; c) selectively excite or depress, reflexly, subpopulations of sympathetic efferent neurons; d) block pharmacologically the whole or part of the sympathetic outflow. Results emerging from our preliminary studies promise significant yield from this research at both basic scientific and applied levels.
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