GDNF levels in the lower lip skin in a rat model of trigeminal neuropathic pain: Implications for nonpeptidergic fiber reinnervation and parasympathetic sprouting

Trigeminal neuropathic pain is associated with trigeminal nerve damage. Significant remodeling of the peripheral nervous system may contribute to the pain; however, the changes and the factors that drive them have not been well described. In this study, a partial injury of the mental nerve of the rat, a purely sensory branch of the trigeminal nerve, resulted in prolonged mechanical allodynia in the lower lip skin persisting up to 4 months. Although nonpeptidergic, P2X3-immunoreactive (IR) C fibers displayed a transient decrease in density of innervation in the skin; they returned to sham levels by 4 weeks after lesioning. Ectopic sympathetic (as detected by anti-dopamine-β-hydroxylase antibodies) and parasympathetic (as detected by antibodies against the vesicular acetylcholine transporter) fibers in the upper dermis were apparent early on the following lesion (2 weeks), in close apposition with regenerating nonpeptidergic fibers. Meanwhile, the glial cell line-derived growth factor (GDNF) showed a quick upregulation in the skin after nerve lesioning, with levels peaking at 4 weeks. This suggests that an excess of GDNF in the skin drives the nonpeptidergic C-fiber regeneration and parasympathetic fiber sprouting in the upper dermis, and could be an important mechanism in trigeminal neuropathic pain. This article provides an in-depth description of the changes in nonpeptidergic fibers in the skin after nerve lesioning, and measures, for the first time, GDNF protein levels in the skin after a nerve lesion, providing strong evidence for the role of GDNF in modulating innervation of the nonpeptidergic and parasympathetic fibers in the skin after injury.