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Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1\u03b2, which subsequently activate sensory neurons to secrete BDNF. To test this hypothesis, we used an animal model of activity-induced pain induced by repeated intramuscular acidic saline injections combined with fatiguing muscle contractions. Intrathecal or intramuscular injection of inhibitors of BDNF-Tropomyosin receptor kinase B (TrkB) signaling, ANA-12 or TrkB-Fc, reduced the decrease in muscle withdrawal thresholds in male, but not in female, mice when given before or 24hr after, but not 1 week after induction of the model. BDNF messenger ribonucleic acid (mRNA) was significantly increased in L4\u2013L6 dorsal root ganglion (DRG), but not the spinal dorsal horn or gastrocnemius muscle, 24hr after induction of the model in either male or female mice. No changes in TrkB mRNA or p75 neurotrophin receptor mRNA were observed. BDNF protein expression via immunohistochemistry was significantly increased in L4\u2013L6 spinal dorsal horn and retrogradely labelled muscle afferent DRG neurons, at 24hr after induction of the model in both sexes. In cultured DRG, fatigue metabolites combined with IL-1\u03b2 significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1\u03b2, BDNF from primary DRG neurons and contribute to activity-induced muscle pain only in males, while there were no sex differences in the changes in expression observed in BDNF.<\/jats:p>","DOI":"10.1101\/2023.10.31.565022","type":"posted-content","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T18:50:11Z","timestamp":1698951011000},"source":"Crossref","is-referenced-by-count":1,"title":["Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice"],"prefix":"10.64898","author":[{"given":"Kazuhiro","family":"Hayashi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph B.","family":"Lesnak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley N.","family":"Plumb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"Janowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela F.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joslyn K.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen A.","family":"Sluka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023110705400575000_2023.10.31.565022v1.1","unstructured":"Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. 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