CELLULAR MECHANISMS OF HYPERALGESIA

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The understanding and treatment of chronic pain remains a formidable medical challenge. Hyperalgesia, an increased pain sensation in response to noxious stimuli, and allodynia, a pain sensation in response to a normally non-noxious stimulus, are two common forms of persistent pain. The overall goal of the proposed research is to elucidate the cellular mechanisms that may underlie hyperalgesia and allodynia in an animal model system. Intracellular recordings will be obtained from dorsal horn neurons in the spinal cord of decerebrated and spinalized rats that are perfused through the vasculature. Perfusion, using a non-pulsatile pump, eliminates respiratory and cardiovascular pulsations that can disrupt intracellular recording, thereby producing an "in vivo" preparation with the intracellular recording stability of an "in vitro" preparation. Long- lasting hyperalgesia (10-60 min) will be evoked by electrical stimulation of C-fibers (20 s, 1 Hz) in the sciatic nerve. Simultaneously, the correlated changes in the cellular properties of the impaled neuron will be monitored by periodically injecting a 3 s pulse of depolarizing current through the micropipette. Plastic alterations in the neurons repetitive firing properties will be indicated by a alteration in the response to the injected current. The Specific Aims are: 1. Determine if changes in cellular properties and synaptic input occur during hyperalgesia. 2. Characterize the specific changes that occur in repetitive firing properties and ionic conductances. 3. Compare the cellular changes that occur in neurons (a) in different lamina, (b) having different types of sensory input, (c) resulting from cutaneous vs. muscle conditioning C-fiber stimulation, and (d) in response to Abeta, Adelta and C-fiber conditioning stimulation. These experiments will further our understanding of cellular mechanisms of plasticity and hyperalgesia and may lead to improved treatments for chronic pain.