Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice
Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice
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DOI：
10.1016/j.neuropharm.2023.109814
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发表时间：
2023-12-18
影响因子：
4.7
通讯作者：
Liu，Zhongjie
中科院分区：
文献类型：
--
作者：
Fan，Keke;Liao，Qinming;Liu，Zhongjie
目前的证据表明，过度活跃或受损的自噬可导致神经元死亡。局麻药对疼痛性糖尿病神经病变（PDN）的影响以及自噬在上述病理过程中的作用尚不清楚，值得进一步研究。因此，通过评估瘦素基因突变（db/db）小鼠的缩爪阈值（PWT）和缩爪潜伏期（PWL）来建立PDN模型。野生型 (WT) 和 PDN 小鼠接受鞘内 0.75% 布比卡因或/腹膜内药物治疗（雷帕霉素或巴弗洛霉素 A1）。随后，在鞘内注射布比卡因后 6 小时、24 小时、30 小时和 48 小时测量 PWT 和 PWL 以评估痛觉过敏。此外，在鞘内布比卡因治疗前和治疗后 48 小时测量感觉神经传导速度 (SNCV) 和运动神经传导速度 (MNCV)。采集L4-L6节段脊髓组织和血清，评价自噬、氧化应激、氧化损伤和凋亡的变化。我们发现布比卡因诱导自噬激活，但不影响 WT 小鼠在预定时间点的痛阈、SNCV 和 MNCV。相反，布比卡因降低了 PDN 小鼠自噬体的生成和降解，减缓了 SNCV 并加重了脊髓背角神经元氧化损伤和痛觉过敏。自噬激活剂（雷帕霉素）可以减轻布比卡因治疗的 PDN 小鼠脊髓背角神经元氧化损伤，减轻 SNCV 和痛觉过敏的改变。同时，自噬抑制剂（巴弗洛霉素A1）可能会加剧布比卡因治疗的PDN小鼠的脊髓背角神经元氧化损伤、SNCV的改变和痛觉过敏。我们的研究结果表明，布比卡因可诱导 PDN 小鼠自噬缺陷，减慢 SNCV 并加重脊髓背角神经元氧化损伤和痛觉过敏。恢复自噬可能是局部麻醉和镇痛 PDN 患者神经损伤的潜在治疗方法。
Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L4-L6segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.