title: Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.
abstract: Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase-2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R(2) = 0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde- and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic, cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians' apparent lower pain tolerance.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Laboratory of Pain and Signaling, Butantan Institute, São Paulo 05503-900, Brazil.
authors.forename: Vanessa O
authors.initials: VO
authors.lastname: Zambelli
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gross
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Laboratory of Pain and Signaling, Butantan Institute, São Paulo 05503-900, Brazil.
authors.forename: Vanessa P
authors.initials: VP
authors.lastname: Gutierrez
authors.affiliation: Laboratory of Pain and Signaling, Butantan Institute, São Paulo 05503-900, Brazil.
authors.forename: Yara
authors.initials: Y
authors.lastname: Cury
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. mochly@stanford.edu.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000079:Acetaldehyde; D059787:Acute Pain / Q000201:enzymology* / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001522:Behavior, Animal; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005557:Formaldehyde; D006579:Heterozygote; D006930:Hyperalgesia / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism*; D059225:Nociception; D051381:Rats
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; D024101:Mitochondrial Proteins; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D005557:Formaldehyde; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D000079:Acetaldehyde