Deficient AMPK activity contributes to hyperexcitability in peripheral nociceptive sensory neurons and thermal hyperalgesia in lupus mice.
Deficient AMPK activity contributes to hyperexcitability in peripheral nociceptive sensory neurons and thermal hyperalgesia in lupus mice.
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DOI：
10.1371/journal.pone.0288356
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
系统性红斑狼疮（SLE）患者经常遭受慢性疼痛。关于SLE引起慢性疼痛的外周机制知之甚少。本研究的目的是探讨是否以及如何在背根神经节（DRG）伤害性神经元的膜特性改变SLE。我们发现，从MRL/lpr小鼠（SLE小鼠模型）与热痛觉过敏的背根神经节的伤害性神经元的静息膜电位，较小的电容，较低的动作电位阈值和rheobases的升高。MRL/lpr小鼠DRG中TNFα、IL-1β和磷酸化ERK的蛋白表达增加，但AMPK活性受到抑制，钠通道1.7蛋白表达无变化。我们发现，足底注射化合物C（AMPK抑制剂）诱导正常小鼠的热痛觉过敏，而足底注射AICAR（AMPK激活剂）减少MRL/Lpr小鼠的热痛觉过敏。AMPK抑制后，正常对照小鼠的伤害性神经元的膜特性可以迅速转换为SLE热痛觉过敏小鼠的膜特性。我们的研究表明，外周伤害性感觉神经元的兴奋性增加有助于SLE小鼠热痛觉过敏的发生，AMPK调节伤害性感觉神经元的膜特性以及SLE小鼠的热痛觉过敏。我们的研究为靶向调节外周伤害性神经元膜特性的信号通路作为征服SLE引起的慢性疼痛的手段提供了基础。
Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain. Little is known about the peripheral mechanisms underlying the genesis of chronic pain induced by SLE. The aim of this study was to investigate whether and how membrane properties in nociceptive neurons in the dorsal root ganglions (DRGs) are altered by SLE. We found elevation of resting membrane potentials, smaller capacitances, lower action potential thresholds and rheobases in nociceptive neurons in the DRGs from MRL/lpr mice (an SLE mouse model) with thermal hyperalgesia. DRGs from MRL/lpr mice had increased protein expressions in TNFα, IL-1β, and phosphorylated ERK but suppressed AMPK activity, and no changes in sodium channel 1.7 protein expression. We showed that intraplantar injection of Compound C (an AMPK inhibitor) induced thermal hyperalgesia in normal mice while intraplantar injection of AICAR (an AMPK activator) reduced thermal hyperalgesia in MRL/Lpr mice. Upon inhibition of AMPK membrane properties in nociceptive neurons from normal control mice could be rapidly switched to those found in SLE mice with thermal hyperalgesia. Our study indicates that increased excitability in peripheral nociceptive sensory neurons contributes to the genesis of thermal hyperalgesia in mice with SLE, and AMPK regulates membrane properties in nociceptive sensory neurons as well as thermal hyperalgesia in mice with SLE. Our study provides a basis for targeting signaling pathways regulating membrane properties of peripheral nociceptive neurons as a means for conquering chronic pain caused by SLE.
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影响因子：
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