NEUROPEPTIDE MODULATION OF CHEMICALLY-INDUCED SKIN IRRITATION

This study addresses the hypothesis that the early symptoms of chemica lly induced skin irritation are neurally mediated. Several approaches were used to affect nerve transmission in adult Balb/c female mice. Th ese included general anesthesia (i.e., sodium pentobarbital), systemic capsaicin treatment, and pretreatment with specific pharmacological a ntagonists of the neuropeptides substance P (SP) and neurokinin A (NKA ). After these treatments, a strongly irritating dose of dinitrofluoro benzene (DNFB) was applied to the ear and its swelling was measured ov er several postexposure times as an index of tissue irritation. Ear sw elling in Nembutal (30 mg/kg)-anesthetized mice was depressed 62 and 7 6% at 4 and 24 hr postexposure compared to DNFB-treated unanesthetized animals measured at the same time points. Multiple injections of caps aicin (cumulative dose 30 mg/kg) depressed DNFB-ear swelling relative to non-capsaicin, DNFB-treated controls by 15, 40 (ip), and 44 and 43% (sc) at 4 and 24 hr postexposure, respectively. In mice exposed to ac ute or multiple injections of the SP antagonist CP-96,345 before DNFB application, ear swelling was depressed (relative to DNFB-treated anim als) by 64 and 36% (acute, sc, 10 mg/kg) and 91 and 88% (multiple, ip, cumulative 35 mg/kg) at 0.5 and 1 hr postexposure, respectively. Mice exposed to the NKA antagonist, SR 48958, alone and in combination wit h the SP antagonist CP-96,345 were also examined after DNFB applicatio n. Ear swelling was diminished in mice pretreated with the NKA antagon ist (1.0 mg/kg) by 17, 24, 34, and 40% at 0.5, 1, 4, and 24 hr postexp osure. When used in combination with the SP antagonist, DNFB-induced e ar swelling was reduced by 95% compared to unantagonized, DNFB-exposed mice at the 0.5- and 1-hr time points and remained significantly depr essed by 33 and 468 at 4 and 24 hr postexposure. Taken in concert, the se data suggest that neuropeptides, especially the tachykinins SP and NKA, modulate the early stages of chemically induced skin irritation. (C) 1995 Academic Press, Inc.