Shubayev Veronica I
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, United States.
Research Service, VA San Diego Healthcare System, La Jolla, CA, United States.
Front Pain Res (Lausanne). 2025 Apr 23;6:1569515. doi: 10.3389/fpain.2025.1569515. eCollection 2025.
The myelin sheath serves both as insulator and metabolic powerhouse for large-diameter dorsal root ganglia (DRG) neurons-some of the longest cells in the body-transmitting sensory impulses from the periphery to the spinal cord. When myelin is damaged, bioactive fragments of myelin basic protein (MBP) are released, playing a pivotal role in pathological pain. MBP-derived peptides (MBPd) emerge as a ubiquitous yet sex-specific mediator of pain. In females, MBPd triggers a widespread transcriptional response across the peripheral nerve, DRG, and spinal cord, leading to persistent, treatment-resistant tactile allodynia-pain from normally innocuous touch. In contrast, males exhibit only a localized transcriptional response, confined to the nerve, which does not extend to the DRG or spinal cord or induce pain. The sex difference is driven by MBPd's interaction with lipids and regulation of nuclear receptor transcription factors, including the estrogen receptor (ESR) and the liver X receptor (LXR)/retinoid × receptor (RXR) complex-key regulators of lipid and cholesterol metabolisms mounting sex-dependent immunity. By unraveling these fundamental mechanisms of myelin remodeling, this work opens the door to innovative, non-addictive, personalized therapeutics and diagnostics for chronic pain.
髓鞘对于大直径背根神经节（DRG）神经元而言，既是绝缘体又是代谢动力源。DRG神经元是人体中最长的一些细胞，负责将感觉冲动从外周传递至脊髓。当髓鞘受损时，髓鞘碱性蛋白（MBP）的生物活性片段会被释放出来，在病理性疼痛中发挥关键作用。MBP衍生肽（MBPd）成为一种普遍存在但具有性别特异性的疼痛介质。在雌性动物中，MBPd会引发外周神经、DRG和脊髓广泛的转录反应，导致持续性、难治性触觉异常性疼痛——由正常情况下无害的触摸引发的疼痛。相比之下，雄性动物仅表现出局限于神经的转录反应，不会延伸至DRG或脊髓，也不会引发疼痛。这种性别差异是由MBPd与脂质的相互作用以及对核受体转录因子的调控所驱动的，这些转录因子包括雌激素受体（ESR）和肝脏X受体（LXR）/视黄酸X受体（RXR）复合物——脂质和胆固醇代谢的关键调节因子，它们会增强性别依赖性免疫。通过揭示髓鞘重塑的这些基本机制，这项研究为慢性疼痛的创新、非成瘾性、个性化治疗和诊断打开了大门。
