The overall goal of our research is to investigate the mechanisms underling sympathetic sprouting and its correlation with ectopic, spontaneous activity originating from axotornized sensory neurons or injured peripheral axons (neuroma). After peripheral axotomy, sympathetic axons sprout into the lumbar dorsal root ganglia (DRGs), a major phenomenon implicated in neuropathic pain (e.g., complex regional pain syndrome [CRPS]). Although there is evidence that certain glial-cell-derived neurotrophins are involved in the sympathetic sprouting, the causal factor that triggers, and possibly guides, the sprouting of sympathetic nerve endings remains largely unknown. However, evidence exists that sympathetic sprouting is associated predominately with large- and medium-sized sensory neurons, which often present with high frequency and/or bursting discharges after nerve injury. Results from our preliminary study revealed that systemic lidocaine (a Na* channel blocker) significantly reduced the extent of sympathetic sprouting, whereas systemic administration of 4-aminopyridine (4-AP, a K+ channel blocker), which enhances spontaneous activity, increased the sprouting. We hypothesize that injury of the peripheral nerve or the DRG causes high frequency and/or bursting discharges in large- and medium-sized DRG neurons that trigger the sprouting of sympathetic nerve fibers possibly through the enhanced expression of neurotrophins from satellite glial cells. Using animal models of experimental neuroma combining with electrophysiological, immunohistochemical and Western blot techniques, we will test our hypothesis via the following 3 Specific Aims.
Specific Aim 1. Examine whether sympathetic sprouting in DRGs with peripheral axotomy shows any preference for spontaneously active neurons with high frequency and/or bursting discharges or hyperexcitability.
Specific Aim 2. Determine whether sympathetic sprouting may be evoked by spontaneous activity in DRGs without axotomy.
Specific Aim 3. Assess the role of glial cell-derived neurotrophins in activity-dependent sympathetic sprouting. If a relationship among spontaneous activity, neurotrophins, and sympathetic sprouting is identified, then new therapeutic approaches involving pharmacological modulation of spontaneous activity could be developed to suppress the hyperexcitability of sensory neurons. Such therapies could provide more effective non-opioid analgesia to patients with neuropathic pain. ? ?
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