The general objective is to use a simple invertebrate model of traumatic neuropathic sensitization to probe fundamental cellular mechanisms that may be important substrates for neuropathic hyperalgesia--a common component of intractable and chronic pain in humans. Various observations, as well as evolutionary arguments, suggest that some basic mechanisms of neuropathic sensitization are likely to be widely conserved. Identified nociceptors and other neurons controlling the tail withdrawal reflex in the mollusc, Aplysia californica, provide a special opportunity to test the roles of specific cellular mediators in the induction, expression, and termination of neuropathic sensitization involving nerve injury. Using this system, a model of neuropathic sensitization involving crush injury of the tail will be developed that allows direct tests of hypotheses about mechanisms underlying expression and induction of persistent behavioral and sensory alterations lasting for months. Tests will be made of the contributions of peripheral changes, including sensitization of afferents, spontaneous discharge of injured axons, and background neuromodulator release. Tests of persistent central changes will examine hyperexcitability of nociceptor somata, interneurons and motor neurons, facilitation of central synapses, disinhibition, and background electrical and synaptic activity. Tests of induction mechanisms will examine contributions of fast, activity-dependent signals, neuromodulator release, long-term synaptic potentiation, and slow axoplasmic signals. A general hypothesis about the combined role of cAMP, calcium ions and slow axoplasmic injury signals in the induction of persistent nociceptor hyperexcitability and enhancement of nociceptor regeneration will be tested in a reduced preparation of ganglia and nerves, and in isolated nociceptors growing in cell culture. Other potential intracellular and extracellular signals for induction and maintenance of persistent nociceptor hyperexcitability will begin to be screened in individual cells.
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