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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 model, in which anatomic nerve regeneration can be easily observed, nicotine reduced anatomic 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 \u03b17 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 a nicotine-treated nerve crush model. Our results reveal that nicotine and its \u03b17-nAChR regulate both peripheral nerve regeneration process and pain though PTEN and the downstream inflammation-related pathway.<\/jats:p>","DOI":"10.1523\/eneuro.0185-23.2023","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T17:50:34Z","timestamp":1692899434000},"page":"ENEURO.0185-23.2023","source":"Crossref","is-referenced-by-count":15,"title":["Nicotine Decreases Nerve Regeneration and Pain Behaviors via PTEN and Downstream Inflammation-Related Pathway in Two Rat Nerve Injury Models"],"prefix":"10.1523","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9840-2136","authenticated-orcid":false,"given":"Yehong","family":"Fang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingkai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhui","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"2023090610500962000_10.9.ENEURO.0185-23.2023.1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/02791072.2016.1172745","article-title":"Nicotine 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