Endometriosis‐associated vaginal hyperalgesia is mediated by the balance of reactive aldehyde production and metabolism.

Abstract

BackgroundEndometriosis affects ~176 million women worldwide and is characterized by the growth of endometrial tissue outside the uterus (known as endometrial ectopic cysts). How endometriosis becomes associated with painful symptoms is not clear. Here we hypothesize that endometriosis‐associated vaginal hyperalgesia is mediated by an imbalance of reactive aldehyde production and metabolism.MethodsTo test this hypothesis, we used female Sprague‐Dawley rats (n=5/group) and subjected them to a cutting‐edge model of behavioral psychophysics to assess for rat vaginal nociception. Prior to subjecting the rodents to this model, we treated rodents with the reactive aldehyde, acetaldehyde (9 mg/kg intraperitoneal) to mimic an increased production of reactive aldehydes in the intraperitoneal space. To modulate ALDH2 activity, we administered to rodents either the ALDH2 activator, Alda‐1 (1 mg/kg, diluted in DMSO, given intraperitoneal) or the ALDH2 inhibitor disulfiram (15 mg/kg, diluted in DMSO, given intraperitoneal). The ALDH2 activator were delivered 10 minutes before or after acetaldehyde (Alda‐1 + aldehyde or aldehyde +Alda‐1). Disulfiram was given 10 minutes before acetaldehyde (Disulfiram + aldehyde). As controls Alda‐1, disulfiram, saline, and DMSO were delivered alone. Changes in vaginal nociception were expressed as area‐under‐the‐curve (AUC) units and calculated using standard trapezoid methods. For statistical analysis, a one‐way ANOVA with Bonferroni's multiple comparison test was used. Data presented as mean ± SEM.ResultsAcetaldehyde‐induced vaginal hyperalgesia (44±4* vs. saline 28±2, *P<0.05). Alda‐1 markedly attenuated hyperalgesia when given either before (26±3, *P<0.05 vs. acetaldehyde) or after (25±3, *P<0.05 vs. acetaldehyde) acetaldehyde treatment. Conversely, pretreatment with disulfiram before acetaldehyde increased vaginal hyperalgesia (61±5, *P<0.05 vs. acetaldehyde). Alda‐1, DMSO, and disulfiram alone produced no significant changes in vaginal nociception.ConclusionsThese data suggest that the mechanism of endometriosis‐induced hyperalgesia is mediated by changes in reactive aldehyde production and metabolism. Increasing ALDH2 activity in rats, both prevented and alleviated reactive aldehyde‐induced vaginal hyperalgesia. These data suggest a potential novel therapeutic for treating endometriosis by targeting reactive aldehyde metabolism.Support or Funding InformationThis work was supported by the National Institutes of Child Health and Human Development K99HD093858 (SLM), a Stanford Women & Sex Differences in Medicine (WSDM) Seed Grant, and an Endometriosis Foundation of America Research Award.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.