The role of skin nociceptive afferent nerves in blister healing.

Because sensory neuropeptides improve survival of critical skin and muscle flaps in rats, skin nociceptive sensory nerve function in blister healing was examined. Sensory nerve ablation by unilateral hindlimb denervation or cutaneous axon reflex enhancement by 14 days systemic nicotine treatment (5 mg kg-1 day-1) decreased and increased, respectively, peripheral motor functions of nociceptive (peptidergic) skin nerves. Effects on nociception were measured by a radiant heat tail-flick test. Axon reflex flares were evoked by transdermal iontophoresis of acetylcholine or noxious electrical stimulation under pentobarbitone 40 mg kg-1 anaesthesia. Resultant changes in cutaneous microvascular blood flux were measured non-invasively by laser Doppler flowmetry. In nicotine-treated rats compared with placebo-treated controls, acetylcholine-evoked axon reflex flare was enhanced by 240% (p < 0.01) without enhancement of electrically evoked flare. Thus, nicotine-sensitized nociceptors show stimulus specificity in their enhancement of neurogenic flare responses. No significant changes were seen in other endothelial-dependent or smooth muscle-dependent microvascular dilator responses. Nicotine-treated rats had prolonged tail-flick withdrawal latencies to noxious radiant heat stimuli compared with placebo-treated controls (p < 0.05), suggesting an antinociceptive or analgesic effect of nicotine-treatment. Neurogenic effects on wound healing rate were assessed by measuring the dimensions of standardized blisters twice daily. The blisters were raised on hindpaw glabrous skin using a constant weight and diameter of compressed dry ice pellet applied for 30 secs at constant force. Dry-ice blisters raised on the hindpaw 14 days post-denervation were significantly slower to heal completely (42 days) than controls (30 days: P < 0.05) and the surrounding inflammation was reduced. By contrast, nicotine-treated rats showed more rapid blister healing (25 days) than controls (30 days), seen only in the later phase after day 15. Finally, resting substance P release from blisters, after direct cutaneous nerve stimulation, appears to be enhanced in nicotine-treated rats. Thus nociceptive innervation appears critical for inflammation and rapid healing of blisters in rat skin. The data signal a possible important role for neuropeptides in these processes and question the function of nicotinic receptors on sensory nerves.