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The Journal of Neuroscience, April 1, 2003, 23(7):2911
Resiniferatoxin Induces Paradoxical Changes in Thermal and Mechanical Sensitivities in Rats: Mechanism of Action
Hui-Lin Pan1, 2, Ghous M. Khan1, Kevin D. Alloway2, and Shao-Rui Chen1 Departments of 1 Anesthesiology and 2 Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850
Resiniferatoxin (RTX), an ultrapotent analog of capsaicin, has been used as a tool to study the role of capsaicin-sensitive C fibers in pain. Recently, we found that RTX diminished the thermal sensitivity but unexpectedly increased the sensitivity to tactile stimulation in adult rats. In this study, we explored the potential mechanisms involved in RTX-induced changes in somatosensory function. An intraperitoneal injection of 200 µg/kg RTX, but not its vehicle, rapidly produced an increase in the paw withdrawal latency to a heat stimulus. Also, profound tactile allodynia developed in all the RTX-treated rats in 3 weeks. This paradoxical change in thermal and mechanical sensitivities lasted for at least 6 weeks. Electron microscopic examination of the sciatic nerve revealed a loss of unmyelinated fibers and extensive ultrastructural damage of myelinated fibers in RTX-treated rats. Immunofluorescence labeling showed a diminished vanilloid receptor 1 immunoreactivity in dorsal root ganglia neurons and the spinal dorsal horn of RTX-treated rats. Furthermore, two transganglionic tracers, horseradish peroxidase conjugates of cholera toxin B subunit (CTB) and isolectin-B4 of Bandeiraea simplicifolia (IB4), were injected into the opposite sides of the sciatic nerve to trace myelinated and unmyelinated afferent terminations, respectively, in the spinal dorsal horn. In RTX-treated rats, IB4-labeled terminals in the dorsal horn were significantly reduced, and CTB-labeled terminals appeared to sprout into lamina II of the spinal dorsal horn. Thus, this study demonstrates that systemic RTX diminishes the thermal pain sensitivity by depletion of unmyelinated afferent neurons. The delayed tactile allodynia induced by RTX is likely attributable to damage to myelinated afferent fibers and their abnormal sprouting in lamina II of the spinal dorsal horn. These data provide new insights into the potential mechanisms of postherpetic neuralgia.
Key words: neuropathic pain; postherpetic neuralgia; capsaicin; VR1 receptor; TRPV channel; spinal cord dorsal horn; axonal sprouting
Copyright © 2003 Society for Neuroscience 0270-6474/03/2372911-09$05.00/0
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