title: 17β-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception.
abstract: Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17β-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Zu-Wei
authors.initials: ZW
authors.lastname: Qu
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Ren
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Gan
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Qiu
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ren
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Rao
authors.affiliation: Institute of Ion Channels (Z.-W.Q., T.-T.L., C.R., X.G., C.-Y.Q., P.R., W.-P.H.), Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, Hubei, People's Republic of China; and Department of Oncology (Z.R.), Wuhan of General Hospital of Guangzhou, People's Liberation Army, Wuhan 430070, People's Republic of China.
authors.forename: Wang-Ping
authors.initials: WP
authors.lastname: Hu
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000187:drug effects* / Q000378:metabolism; D000138:Acidosis; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists; D047629:Estrogen Receptor beta / Q000819:agonists; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects*; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D058748:Pain Perception / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D012737:Sex Factors; D011422:Propionates
chemical_list: D019342:Acetic Acid; D062565:Acid Sensing Ion Channels; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol