Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism

Abstract

Mutations in Nav1.9 encoded by SCN11A have been associated with episodic pain, small-fiber neuropathy, and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. The SCN11A mutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in 3 patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through noninactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a A796G/A796G mice. The Scn11a A796G/A796G mice showed increased sensitivity to mechanical, heat, and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNav1.9 channel current and excitability of Scn11a A796G/A796G mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a A796G/A796G mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a A796G/A796G mice. These results indicated that Scn11a A796G/A796G mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.

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

“…Amongst ethanol metabolites, acetaldehyde has been described as the most active metabolite in regulating nociception. 10 , 11 Local injection of acetaldehyde increases pain hypersensitivity in rodents, 9 , 10 which is unlikely to contribute to the analgesic effect of ethanol. Astrocyte ALDH2 deficiency did not affect serum or spinal acetaldehyde content.…”

“…ALDH2 deficiency in humans and rodents is associated with increased pain sensitivity to various noxious stimuli. 9 , 10 Deficiency of ALDH2 results in serum and tissue acetaldehyde elevation and acetate ablation. 11 , 12 Although elevated acetaldehyde is found to produce peripheral neuronal inflammation and pain hypersensitivity, 10 little is known about the role of acetate in pain modulation.…”

Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention

“…Guanine at the 1510 th nucleotide position (from the initiation codon) in exon 12 of the human ALDH2 gene is replaced by adenine (G → A), which changes codon 487 from GAA to AAA, leading to a glutamic to lysine amino acid change (Glu → Lys) [ 65 , 95 ]. The Glu487Lys SNP of ALDH2 (also known as Glu504Lys, rs671, c.1510G > A, p.E504K) [ 65 , 96 ] changes the wild-type (WT) allele ALDH2*1 into the mutant allele ALDH2*2 , resulting in a decrease or loss of catalytic activity of the ALDH2 tetrameric enzyme ( Figure 2 B) [ 97 ]. As a result, three genotypes are produced: WT homozygous ALDH2*1/1 , mutant heterozygous ALDH2*1/2 , and mutant homozygous ALDH2*2/2 [ 98 , 99 , 100 ].…”

Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9

“…Scn11a 2/2 mice were kindly provided by Patrick Delmas. 27 Scn11A A796G/A796G mice were described earlier, 42 and Scn11a 1/1 mice (C57BL/6J) were purchased from Hubei Provincial Center for Disease Control and Prevention (Wuhan, China). All animals were housed under 12-hour light/dark cycles with free access to food and water.…”

“…Dorsal root ganglion neurons were dissected and subjected to conventional whole-cell patch-clamp recordings by using an Axopatch 200b amplifier as described in our previous studies. 42,44 Equal numbers of male and female mice were used. Protein arginine methyltransferase 7 or the control vector was mixed with hNa V 1.9 at a ratio of 10:2 and then electroporated into Scn11a 2/2 mouse DRG neurons by using the Neon transfection system (Life Technologies).…”