Department of Anesthesiology, Second Affiliated Hospital of Anhui Medical University, Hefei, China; Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Laboratory for Metabolic Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Br J Anaesth. 2021 Aug;127(2):296-309. doi: 10.1016/j.bja.2021.02.035. Epub 2021 Apr 29.
Little is known about the targets in the CNS that mediate ethanol analgesia. This study explores the role of spinal astrocyte aldehyde dehydrogenase-2 (ALDH2), a key ethanol-metabolising enzyme, in the analgesic effects of ethanol in mice.
Astrocyte and hepatocyte ALHD2-deficient mice were generated and tested in acute and chronic pain models. Cell-type-specific distribution of ALDH2 was analysed by RNA in situ hybridisation in spinal slices from astrocytic ALDH2-deficient mice and their wild-type littermates. Spinal ethanol metabolites and γ-aminobutyric acid (GABA) content were measured using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry.
ALDH2 mRNA was expressed in both astrocytes and neurones in spinal cord slices. Astrocyte ALDH2-deficient mice had decreased expression of ALDH2 mRNA in astrocytes, but not in neurones. Astrocyte ALDH2 deficiency inhibited ethanol-derived acetate, but not acetaldehyde content in spinal cord tissues. Depletion of spinal astrocyte ALDH2 selectively inhibited ethanol-induced anti-nociceptive effect, but not the effect of ethanol, on motor function. Astrocyte ALDH2 deficiency abolished ethanol-induced GABA elevation. The ethanol metabolite acetate produced anti-nociception and increased GABA synthesis in a manner similar to ethanol. I.T. delivery of either GABA or GABA receptor antagonists prevented ethanol and acetate-induced analgesia.
These findings provide evidence that ALDH2 in spinal astrocytes mediates spinal ethanol metabolism and ethanol-induced analgesic effects by promoting GABA synthesis and GABAergic transmission in spinal cord.
中枢神经系统（CNS）中介导乙醇镇痛的靶点知之甚少。本研究探讨了脊髓星形胶质细胞乙醛脱氢酶-2（ALDH2）作为关键的乙醇代谢酶在乙醇对小鼠镇痛作用中的作用。
生成了星形胶质细胞和肝细胞 ALDH2 缺陷型小鼠，并在急性和慢性疼痛模型中进行了测试。通过 RNA 原位杂交分析从星形胶质细胞 ALDH2 缺陷型小鼠及其野生型同窝仔鼠的脊髓切片中分析 ALDH2 的细胞类型特异性分布。使用气相色谱/质谱和液相色谱/质谱测量脊髓乙醇代谢物和γ-氨基丁酸（GABA）含量。
ALDH2 mRNA 在脊髓切片中的星形胶质细胞和神经元中均有表达。星形胶质细胞 ALDH2 缺陷型小鼠的星形胶质细胞中 ALDH2 mRNA 表达减少，但神经元中没有。星形胶质细胞 ALDH2 缺陷抑制脊髓组织中乙醇衍生的乙酸盐，但不抑制乙醛含量。脊髓星形胶质细胞 ALDH2 耗竭选择性抑制乙醇诱导的抗伤害作用，但不抑制乙醇对运动功能的作用。星形胶质细胞 ALDH2 缺陷消除了乙醇诱导的 GABA 升高。乙醇代谢物乙酸盐以类似于乙醇的方式产生抗伤害作用并增加 GABA 合成。鞘内给予 GABA 或 GABA 受体拮抗剂可预防乙醇和乙酸盐诱导的镇痛。
这些发现提供了证据表明，脊髓星形胶质细胞中的 ALDH2 通过促进脊髓中 GABA 的合成和 GABA 能传递，介导脊髓中的乙醇代谢和乙醇诱导的镇痛作用。
