Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Solomon H. Snyder Department of Neuroscience and Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Int J Mol Sci. 2023 Sep 6;24(18):13760. doi: 10.3390/ijms241813760.
Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests showed that early isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. Immunohistochemistry, Western blotting, and q-PCR indicated that isoflurane upregulated mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We concluded that early GA exposure, at least with isoflurane, alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.
在生命早期接受过手术的患者在以后的生活中可能会面临更高的神经病理性疼痛风险。这种易感性的风险因素尚未完全了解。在这里，我们使用小鼠慢性疼痛模型来检验以下假说，即在生命早期接触全身麻醉剂（GA）异氟烷会导致背根神经节（DRG）和背角（DSC）中的细胞和分子改变，通过上调哺乳动物雷帕霉素靶蛋白（mTOR）信号通路导致易患神经病理性疼痛。小鼠在出生后第 7 天（P7）暴露于异氟烷中，并在 P28 时进行神经损伤保留（ spared nerve injury ），从而导致慢性疼痛。选择的组用雷帕霉素（mTOR 抑制剂）治疗八周。行为测试表明，早期异氟烷暴露会增加慢性疼痛的易感性，而雷帕霉素治疗可以改善结果。免疫组织化学，Western blot 和 q-PCR 表明，异氟烷上调了 DSC 和 DRG 中的 mTOR 表达和神经活性。mTOR 的上调以及与慢性疼痛相关的标志物（包括 N-钙黏蛋白、cAMP 反应元件结合蛋白（CREB）、嘌呤能 P2Y12 受体、胶质纤维酸性蛋白（GFAP））的雷帕霉素可逆转变化，在 DSC 中观察到；以及连接蛋白 43、磷酸化细胞外信号调节激酶（p-ERK）、GFAP、DRG 中的 Iba1。我们得出结论，早期 GA 暴露（至少是异氟烷）改变了疼痛回路的发育，使得小鼠随后更容易受到慢性神经病理性疼痛状态的影响。
