TY - JOUR
T1 - Estrogen metabolites increase nociceptor hyperactivity in a mouse model of uterine pain
AU - Xie, Zili
AU - Feng, Jing
AU - Cai, Tao
AU - McCarthy, Ronald
AU - Eschbach, Mark D.
AU - Wang, Yuhui
AU - Zhao, Yonghui
AU - Yi, Zhihua
AU - Zang, Kaikai
AU - Yuan, Yi
AU - Hu, Xueming
AU - Li, Fengxian
AU - Liu, Qin
AU - Das, Aditi
AU - England, Sarah K.
AU - Hu, Hongzhen
N1 - Publisher Copyright:
© 2022, Xie et al.
PY - 2022/5/23
Y1 - 2022/5/23
N2 - 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 estrogeninduced uterine pain model. Importantly, pretreatment with 2- or 4-OHE1 recapitulated estrogeninduced 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.
AB - 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 estrogeninduced uterine pain model. Importantly, pretreatment with 2- or 4-OHE1 recapitulated estrogeninduced 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.
UR - http://www.scopus.com/inward/record.url?scp=85130731050&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.149107
DO - 10.1172/jci.insight.149107
M3 - Article
C2 - 35420999
AN - SCOPUS:85130731050
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 10
M1 - e149107
ER -