Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Pain. 2024 Apr 1;165(4):893-907. doi: 10.1097/j.pain.0000000000003091. Epub 2023 Oct 20.
Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions.
伤害感受器细胞体产生“自发性”放电，可促进持续性疼痛情况下的持续性疼痛。目前对于潜在机制知之甚少。从啮齿动物和人类背根神经节分离的伤害感受器细胞体（胞体）的记录表明，体内先前的疼痛与由膜电位（DSF）不规则去极化自发波动控制的低频放电有关，这种波动可能是由穿过胞体输入电阻的瞬时内向电流产生的。使用小鼠伤害感受器，我们表明 DSF 与高胞体输入电阻相关，范围广泛的膜电位，包括接近动作电位（AP）阈值的去极化水平。在表现出自发活动的神经元中，输入电阻以及 DSF 的幅度和频率均增加。离子替代实验表明，DSF 的去极化相是由对 Na + 或 Ca 2+ 通透的通道的自发开放产生的，并且 Ca 2+ 通透通道对较大的 DSF 特别重要。通过灌流药理学抑制剂部分降低 DSF 的幅度或频率表明，Nav1.7、Nav1.8、TRPV1、TRPA1、TRPM4 和 N 型 Ca 2+ 通道的贡献较小但很重要。不太特异的阻滞剂表明 NALCN 通道的贡献，而全局敲除表明 Nav1.9 的作用。高胞体输入电阻加上对 Na + 或 Ca 2+ 通透的多种离子通道的背景活性的组合产生 DSF，如果静息膜电位去极化、AP 阈值降低或 DSF 增强，则 DSF 就会达到 AP 阈值-所有这些都可能发生在疼痛性神经病变和炎症条件下。
