Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

Autor(es)

Zambelli, Vanessa O. ^{[1, 2]} ; Gross, Eric R. ^{[1, 3]} ; Chen, Che-Hong ^[1] ; Gutierrez, Vanessa P. ^[2] ; Cury, Yara ^[2] ; Mochly-Rosen, Daria ^[1]

Afiliação do(s) autor(es)

^[1] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA

^[2] Butantan Inst, Lab Pain & Signaling, BR-05503900 Sao Paulo - Brazil

^[3] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 - USA

• Tipo de documento: Artigo Científico
• Fonte: Science Translational Medicine; v. 6, n. 251 AUG 27 2014.
• Citações Web of Science: 32

Resumo

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 similar to 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. (AU)

• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 11/08873-8 - Papel da aldeído desidrogenase 2 e do 4-hidroxinonenal na dor
• Beneficiário: Vanessa Olzon Zambelli
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/05035-4 - Papel da aldeído desidrogenase 2 e do 4-hidroxinonenal na dor
• Beneficiário: Yara Cury
• Modalidade de apoio: Auxílio à Pesquisa - Regular