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NEUROPEPTIDE MODULATION OF CHEMICALLY INDUCED SKIN IRRITATION
Citation:
Veronesi, B., D. Sailstad, D.L. Doerfler, AND M. Selgrade. NEUROPEPTIDE MODULATION OF CHEMICALLY INDUCED SKIN IRRITATION. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-96/042.
Description:
This study was designed to demonstrate that the early symptoms of chemically-induced skin irritation are neurally mediated. everal approaches were used to affect nerve transmission in adult Balb/c female mice. hese included general anesthesia (i.e., sodium pentobarbital), systemic capsaicin treatment, and pretreatment with specific pharmacological antagonists of substance P (SP) and neurokinin A (NKA). fter these treatments, a strong irritating dose of dinitrofluorobenzene (DNFB) was applied to the ear and its swelling was measured over several post-exposure times as an index of tissue irritation. ar swelling in Nembutal (30 mg/kg) anesthetized mice was depressed 62% and 76% at 4 and 24 hr post-exposure compared to DNFB-treated unanesthetized animals at the same time points. ultiple injections of capsaicin (cumulative dose 30 mg/kg) depressed DNFB-ear swelling relative to non-capsaicin, DNFB-treated controls by 15%, 40% (IP) and 44%, 43% (SC) at 4 and 24 hr post-exposure, respectively In mice exposed to acute or multiple injections of the SP antagonist CP-96,345 before DNFB application, ear swelling was depressed (relative to DNFB treated animals) by 64% and 36% (acute, SC, 1 0 mg/kg); and 91 % and 88% (multiple, IP, cumulative 35 mg/kg) at 0.5 and 1 hr post-exposure. ice exposed to the NKA antagonist, SR 48968 alone and in combination with the SP antagonist CP-96,345 were also examined after DNFB application. ar swelling was diminished in mice pretreated with the NKA antagonist (1.0 mg/kg) by 17%, 24%, 34% and 40% at 0.5, 1, 4 and 24 hr post-exposure. hen used in combination with the SP-antagonist, DNFB-induced ear swelling was reduced by 95% compared to unantagonized, DNFB-exposed mice at the 0.5 and 1 hr time points and remained significantly depressed by 33% and 46% at 4 and 24 hr post-exposure. aken in concert, these data suggest that neuropeptides, especially the tachykinins SP and NKA, play a decisive role in the early stages of chemically-induced skin irritation.