Transient Receptor Potential Vanilloid-1 Channel Blockade in the Peripheral Nerve Terminal by Resiniferatoxin for the Treatment of Chronic Pain
Chelsea C. Snider, MD1; Louis S. Premkumar, PHD2; Michael Neumeister, MD, FRCSC, FACS1
1Institute for Plastic Surgery, Southern Illinois University, School of Medicine, Springfield, IL; 2Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield, IL
Background: Expression of TRPV-1 channels in peripheral nerve terminals is responsible for transducing thermal and chemical nociception. Various systemic chemical antagonists of the TRPV-1 receptor have been trialed for the treatment of chronic pain; however, they lead to increased basal body temperature and fevers. We have previously shown that TRPV-1 activity and pain signaling is reduced in the presence of botulinum toxin; however, adverse effects of botulinum toxin include local muscle paralysis. Recent emergence of resiniferatoxin (RTX) has shown to activate TRPV-1 in an irreversible manner and lead to ablation at the nerve terminal. With its low side-effect profile, we hypothesize that RTX may be used to target TRPV-1 nociceptive pathways in the peripheral nerve to treat chronic pain conditions such as complex regional pain syndrome, neuromas, and arthritis.
Methods: Increasing concentrations of RTX were injected into the plantar surface of the hind paw of wild-type mice. Capsaicin-induced nocifensive behavior was recorded. Response latencies to thermal stimulation in RTX-injected and control mice and were measured with a radiant heat apparatus. Dorsal root ganglion and plantar skin of the hind paw were stained for TRPV-1 for immunohistochemistry analysis and confocal imaging. Experiments were repeated with TRPV-1 knockout mice. Statistical significance was defined as p<0.05.
Results: Dose-dependent loss of capsaicin-induced nocifensive hehavior was observed on day two following RTX administration. Capsaicin-induced nocifensive behavior gradually recovered to its basal level over a period of 63 days. Enhanced response latency to radiant heat was observed two days following RTX treatment. Response latency decreased gradually over a two-month period. Control mice injected with saline showed no change in response latency when subjected to the radiant heat test. TRPV-1 knockout mice showed moderate decrease in response latency as compared to RTX-treated mice. Immunohistochemistry analysis demonstrated no staining for TRPV-1 in paw skin after two days from RTX injection; however, TRPV-1 nerve fibers demonstrated regeneration over a two-month period. There was no change in the number of dorsal root ganglion TRPV-1 expressing cell bodies or the intensity of staining of these cell bodies.
Conclusions: This research investigates the effects of RTX on nociceptive targets in the peripheral nerve that mediate and sensitize pain signaling. In this study we have determined the role of TRPV-1 nerve terminal expression. RTX administration temporarily ablates TRPV-1 expressing peripheral nerve fibers without affecting their regeneration capacity. This provides novel therapeutic perspectives for treating chronic pain pathologies involving the peripheral nervous system.
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