Estrogen metabolites increase nociceptor hyperactivity in a mouse model of uterine pain

作者全名："Xie, Zili; Feng, Jing; Cal, Tao; McCarthy, Ronald; Eschbach, Mark D., III; Wang, Yuhui; Zhao, Yonghui; Yi, Zhihua; Zang, Kaikai; Yuan, Yi; Hu, Xueming; Li, Fengxian; Liu, Qin; Das, Aditi; England, Sarah K.; Hu, Hongzhen"

作者地址："[Xie, Zili; Feng, Jing; Cal, Tao; Wang, Yuhui; Zhao, Yonghui; Yi, Zhihua; Zang, Kaikai; Yuan, Yi; Hu, Xueming; Li, Fengxian; Liu, Qin; Hu, Hongzhen] Washington Univ, Sch Med, Ctr Study Itch & Sensory Disorders, St Louis, MO 63110 USA; [Xie, Zili; Feng, Jing; Cal, Tao; Wang, Yuhui; Zhao, Yonghui; Yi, Zhihua; Zang, Kaikai; Yuan, Yi; Hu, Xueming; Li, Fengxian; Liu, Qin; Hu, Hongzhen] Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO USA; [Feng, Jing] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai, Peoples R China; [Cal, Tao] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [McCarthy, Ronald; England, Sarah K.] Washington Univ, Sch Med, Ctr Reprod Hlth Sci, Dept Obstet & Gynecol, St Louis, MO USA; [Eschbach, Mark D., III; Das, Aditi] Univ Illinois, Neurosci Program, Dept Bioengn, Urbana, IL USA; [Wang, Yuhui] Chinese Acad Med Sci & Peking Union Med Coll, Dept Anesthesiol Plast Surg Hosp, Beijing, Peoples R China; [Yi, Zhihua] Nanchang Univ, Coll Med, Dept Nursing, Nanchang, Jiangxi, Peoples R China"

通信作者："Hu, HZ (通讯作者)，Washington Univ, Sch Med, Ctr Study Itch & Sensory Disorders, Dept Anesthesiol, 660 South Euclid Ave,Box 8054, St Louis, MO 63110 USA."

来源：JCI INSIGHT

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000802211300001

JCR分区：Q1

影响因子：8

年份：2022

卷号：7

期号：10

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Pain emanating from the female reproductive tract is notoriously difficult to treat, and the prevalence of transient pelvic pain has been placed as high as 70%???80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here, we showed that the pain-initiating TRPA1 channel was required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2-and 4-hydroxylated estrogen metabolites (2-and 4-HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol, or 16-HEMs, directly increased nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2-and 4-hydroxylation estrone (2-or 4-OHE1) could sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 were expressed in uterine-innervating primary nociceptors, and their expression was increased in the estrogen induced uterine pain model. Importantly, pretreatment with 2-or 4-OHE1 recapitulated estrogen induced uterine pain-like behaviors, and intraplantar injections of 2-and 4-OHE1 directly produced a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrated that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain."

基金机构："NIH [R01DK103901, R01AR077183, R01AA027065]; Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine in St. Louis"

基金资助正文："This work was supported by grants from the NIH (R01DK103901, R01AR077183, and R01AA027065) and Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine in St. Louis to HH."