Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice.
Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice.
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脑源性神经营养因子会导致雄性小鼠活动引起的肌肉疼痛，但雌性小鼠则不会。
DOI：
10.1101/2023.10.31.565022
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sluka,KathleenA
中科院分区：
文献类型：
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作者：
Hayashi,Kazuhiro;Lesnak,JosephB;Plumb,AshleyN;Janowski,AdamJ;Smith,AngelaF;Hill,JoslynK;Sluka,KathleenA
活动性肌肉疼痛可增加肌肉巨噬细胞释放白细胞介素1β(IL-1β)，阻断IL-1β可阻止疼痛的发生。脑源性神经营养因子是在IL-1β作用下从感觉神经元释放出来的一种神经营养因子，可介导炎症性和神经病理性疼痛。因此，我们假设疲劳肌肉收缩时释放的代谢物激活巨噬细胞释放IL-1β，继而激活感觉神经元分泌脑源性神经营养因子。为了验证这一假设，我们使用了一种动物模型，这种动物模型是通过反复肌肉内注射酸性盐水并结合疲劳性肌肉收缩而引起的活动诱导的疼痛。鞘内或肌肉内注射BDNF-原肌球蛋白受体激酶B(TrkB)信号抑制剂，ANA-12或TrkB-Fc，可减少雄性小鼠肌肉戒断阈值的下降，但雌性小鼠在模型诱导前或24小时后给予ANA-12或TrkB-Fc，但不是在模型诱导后1周。造模24小时后，无论雌雄小鼠L4-L6背根节(DRG)BDNF信使核糖核酸(MRNA)表达均显著增加，而脊髓背角和腓肠肌则无明显变化。TrkB和p75神经营养素受体基因表达无明显变化。免疫组织化学结果显示，造模后24小时，L4-L6脊髓背角和逆行标记的背根节肌肉传入神经元中BDNF蛋白表达均显著增加。在培养的背根神经节中，疲劳代谢产物联合IL-1β显著增加了两性背根神经节中脑源性神经营养因子的表达。综上所述，疲劳代谢产物与IL-1β、脑源性神经营养因子一起从原代背根神经节神经元释放出来，并且只在男性中参与活动诱导的肌肉疼痛，而在观察到的脑源性神经营养因子的表达变化中没有性别差异。
Activity-induced muscle pain increases release of interleukin-1β (IL-1β) in muscle macrophages and the development of pain is prevented by blockade of IL-1β. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1β, 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–L6 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–L6 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-1β significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1β, 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.