Alcohol Metabolizing Enzyme Does Double Duty to Quell Pain
Over half a billion people carry a genetic mutation in an enzyme crucial to alcohol metabolism: aldehyde dehydrogenase-2 (ALDH2). People with the inactive enzyme, including an estimated one-third of East Asians, experience a red skin flush when they indulge in a tipple, but could the common mutation also alter their experience of pain? Daria Mochly-Rosen and colleagues now show that the enzyme’s aldehyde-busting activity dampens inflammatory pain, at least in rodents. Remarkably, Alda-1, an ALDH2-activating compound, alleviated pain in two models of acute inflammatory pain in animals.
Ru-Rong Ji, a researcher at Duke University Medical Center, Durham, US, who was not involved in the new study, called it “fascinating, [with] great potential for human translation,” in an email to PRF. The new work appeared August 27 in Science Translational Medicine.
If the findings do translate to humans—that is, if ALDH2 activity is shown to regulate pain in people, and if Alda-1 can boost ALDH2 activity, the compound could turn out to be a new kind of pain reliever.
Mochly-Rosen and co-first authors Vanessa Zambelli and Eric Gross, all at Stanford University, Palo Alto, US, genetically engineered mice to carry a mutation that swaps glutamine for lysine at position 487 in one copy of the ALDH2 gene, mimicking the human mutation. The researchers saw no difference between the baseline pain thresholds of mutant and wild-type mice. But distinctions emerged when they injected mice in the paw with carrageenan, which causes painful inflammation. Mice with the ALDH2 mutation showed greater sensitivity to mechanical probing of the paw three hours after the injection compared to wild-type mice. That result suggested that the enzyme normally acts to put a brake on inflammatory pain.
The job of ALDH2 is to lower the level of reactive aldehydes in tissues. Accordingly, the researchers detected higher levels of the aldehyde 4-hydroxynonenal (4-HNE) in the paw of mutant mice with the defective form of the enzyme.
Remarkably, the study showed that Alda-1, a small molecule activator of ALDH2, righted the aldehyde-processing deficit and reduced the heightened pain sensitivity displayed by the mutant mice. The drug worked by lowering the aldehyde load in the paw, but it did not reduce inflammation per se.
The researchers also tested Alda-1 in rats with wild-type ALDH2 that received an inflammatory injection of carrageenan or formalin. Similar to the mutant mice, the rats’ pain was reduced by the ALDH2-boosting drug. Those results show that, in addition to fixing inadequate aldehyde processing by the mutant enzyme, the compound could also improve pain by increasing activity of the normal enzyme. Alda-1 also worked to reduce established inflammatory pain in the rats. Mochly-Rosen previously reported that Alda-1 stabilizes the mutant protein, restoring its aldehyde-busting activity, and also promotes activity of the wild-type protein (Perez-Miller et al., 2010).
The researchers detected acetaldehyde in animals’ paws that doubled after carrageenan injection—which was surprising, because acetaldehyde is primarily thought of as a byproduct of alcohol metabolism and not an endogenously produced inflammatory mediator. Alda-1 lowered the level of acetaldehyde in the paw and, along with it, reduced pain behaviors.
Structure of Alda-1 bound to the ALDH2 tetramer. Ribbon diagram shows the ALDH2 subunits in different colors and the four bound Alda-1 molecules in gray. Adapted from Perez-Miller et al., Nat Struct Biol, 2010.
Aldehydes were already known to evoke pain, but ALDH had not previously been studied in pain research, said Pierangelo Geppetti, a pain researcher at Florence University, Italy, who was not involved in the current work. Geppetti and others have reported that aldehydes activate pain pathways via the transient receptor potential channel ankyrin 1 (TRPA1; Bang et al., 2007; Trevisani et al., 2007). “Those findings highlighted the possibility that regulation of aldehyde metabolism may affect pain signaling under conditions of inflammation or tissue injury,” Geppetti told PRF in an email. In the current work, he added, the authors hypothesized that ALDH2 regulates inflammatory pain, and “genetic and pharmacological results robustly corroborated that hypothesis.”
The new work shows that Alda-1 can lessen acute inflammatory pain in rodents, and Mochly-Rosen suspects that it might be effective against other types of pain as well. She and others plan to expand study of the compound to models of chronic and neuropathic pain. Also unknown is whether Alda-1 will work in people, but Mochly-Rosen is hopeful that the compound will one day be tested in clinical trials, which will require licensing of the compound by a pharmaceutical company.
The next step toward human translation will be to investigate whether people with the ALDH2 mutation—all descendants of the Han Chinese—experience greater pain sensitivity than people with the wild-type gene. Anecdotal evidence suggests that some Asians are more susceptible to pain, but until now researchers had chocked the differences up to cultural and social influences (Chan et al., 2013).
What about alcohol? Could drinking exacerbate chronic pain in people with or without the genetic mutation? “Considering that one in five people has chronic pain, and eight in 10 people drink,” said Mochly-Rosen, that question is worthy of future investigation.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.
Image credit: Alda-1
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