Spinal astrocyte aldehyde dehydrogenase-2 mediates ethanol metabolism and analgesia in mice

Abstract

Background: 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. Methods: 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 ALDH2deficient mice and their wild-type littermates. Spinal ethanol metabolites and g-aminobutyric acid (GABA) content were measured using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. Results: 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 A or GABA B receptor antagonists prevented ethanol and acetate-induced analgesia. Conclusions: 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.

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

“…In our study, we did not investigate which are the main cells expressing PKCε-ALDH2 in the paw tissue, however, mitochondria are widely transported along axons and dendrites to the regions of higher energy demands, such as injured tissue. However, although neurons express ALDH2, there is recent evidence showing that spinal astrocytic ALDH2, but not neuronal, mediates alcohol-induced analgesia via acetate-GABA metabolic pathway [ 45 ]. Therefore, the ALDH2 functions go beyond aldehyde detoxification in the pathophysiology of pain.…”

A critical review of ethanol effects on neuronal firing: A metabolic perspective

“…While ADH can be detected immunocytochemically in brain (Buhler et al, 1983), activity studies conclude that the dominant class of enzyme in brain is the low-affinity Class III ADH, which is likely to be ineffective at ethanol concentrations found in tissues (Giri et al, 1989). Ethanol metabolized in astrocytes has been reported by others (Fonseca et al, 2001;Jin, Cao, et al, 2021), and studies have shown that astrocyte metabolism also underlies behavioral effects of ethanol (Jin, Cao, et al, 2021;Jin, Cinar, et al, 2021), but we will focus here on its metabolism in neurons. Recent results from Sun and colleagues (Sun et al, 2023) agree with previous findings (Howard et al, 2003), that CYP2E1 is uniquely induced in pyramidal neurons of the prefrontal cortex upon chronic ethanol exposure.…”

Use and co-use of alcohol and cannabis following physical pain in the daily life of community adults engaged in regular substance use.

“…Compared to cannabis, alcohol may be less perceived as linked to pain relief. However, alcohol has established analgesic properties (Jin et al, 2021), and laboratory pain-induction studies find that alcohol administration, compared to placebo, is associated with greater pain relief, higher pain threshold, and lower pain intensity (Thompson et al, 2017; Vitus et al, 2022; Williams et al, 2021). Acute pain induction also increases motivation to consume alcohol (Gilmour et al, 2022; Moskal et al, 2018; Stennett et al, 2021).…”