The broad objective of this revised renewal proposal is to establish the pharmacological conditions for nerve block that produce preferential sensory or motor impairment in vivo and to investigate the electrophysiological changes in peripheral nerve fibers that underlie these impairments. There are three hypotheses: A. Afferent impulses in both non-myelinated C """"""""nociceptors"""""""" and myelinated mechanosensitive fibers are necessary to elicit withdrawal responses to noxious stimuli; B. The output activity of central (dorsal horn) neurons and peripheral (skeletal muscle) integrators of peripheral axon impulses is not proportional to impulse frequency in nociceptors or motor axons; and C. Local anesthetic inhibition of C-nociceptors is potentiated by agents that directly or indirectly increase intracellular Ca++ and thus modify TTX-insensitive Na+ channels. There are 6 specific aims: 1) Identify with behavioral assays the drugs and conditions that give a functionally selective deficit or impairment. 2) Record electrical changes in functionally identified afferent sensory and efferent somato-motor axons in peripheral nerve in situ during selective impairment. 3) Record changes in electrical responses of nociceptive second order units in spinal dorsal horn during selective impairment. 4) Record changes in muscle electrical responses to afferent peripheral nerve and efferent ventral root stimulation during selective impairment. 5) Measure the changes in Na+ and K+ currents induced by drugs in different types of sensory neurons. 6) Measure content and distribution of drugs in peripheral nerve at different times during selective blocking procedures. Drugs to be tested include traditional local anesthetics (lidocaine and bupivacaine) in combination with capsaicin (a vanilloid receptor agonist), tetrodotoxin and saxitoxin (selective sodium channel antagonists), and veratridine and cevadine (sodium channel activators).
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