Nicotine decreases nerve regeneration and pain behaviors via PTEN and downstream inflammation-related pathway in two rat nerve injury models.

Neuropathic pain is stubborn and associated with peripheral nerve regeneration process. Nicotine has been found to reduce pain but whether it is involved in the regulation of nerve regeneration and the underlying mechanism are unknown. In this study, we examined the mechanical allodynia, thermal hyperalgesia together with the peripheral nerve regeneration after nicotine exposure in two rat neuropathic pain models. In the spinal nerve ligation (SNL) model, in which anatomical nerve regeneration can be easily observed, nicotine reduced anatomical measures of regeneration as well as expression of regeneration marker growth associated protein 43 (GAP43). In the tibial nerve crush model, nicotine treatment significantly suppressed GAP43 expression and functional reinnervation as measured by myelinated action potential and electromyography of gastrocnemius. In both models, nicotine treatment reduced macrophage density in the sensory ganglia and peripheral nerve. These effects of nicotine were reversed by the selective α7 nicotinic acetylcholine receptor (nAChR) blocker, methyllycaconitine. In addition, nicotine significantly elevated expression of PTEN (the phosphatase and tensin homolog deleted on chromosome 10), a key player in both regeneration and pain. Pharmacological interference of PTEN could regulate GAP43 expression, pain related behaviors and macrophage infiltration in nicotine-treated nerve crush model. Our results reveal that nicotine and its α7-nAChR regulate both peripheral nerve regeneration process and pain though PTEN and downstream inflammation-related pathway. Significance Statement Active peripheral nerve regeneration process is closely related to neuropathic pain. Nicotine has demonstrated pain relief properties, but whether nicotine is involved in peripheral nerve regeneration and whether this is related to its analgesic effect are unknown. In two rat nerve injury models, nicotine exposure not only reduced pain behaviors but also inhibited nerve regeneration process in an α7 nicotinic acetylcholine receptor (nAChR)-dependent manner. In addition, nicotine significantly elevated expression of PTEN, a phosphatase and tensin homolog deleted on chromosome 10, and pharmacological interfering with PTEN reversed the inhibitory effect of nicotine on nerve regeneration. These findings provide a novel mechanistic understanding of nicotine's peripheral effect on both peripheral nerve regeneration and pain.