Estrogens Exacerbate Nociceptive Pain via Up-Regulation of TRPV1 and ANO1 in Trigeminal Primary Neurons of Female Rats.
Several trigeminal pain disorders show sex differences, and high levels of estrogens may underlie these differences. The interaction between transient receptor potential vanilloid 1 (TRPV1) and anoctamin 1 (ANO1) plays an important role in peripheral nociception. However, whether TRPV1 and ANO1 are involved in estrogen-modulated trigeminal pain sensitivity is unclear. In this study, we examined estradiol (E2) modulation of nociception through behavioral and immunohistological experiments after application of capsaicin (Cap), a selective TRPV1 agonist, onto the ocular surface in ovariectomized rats treated with high-dose E2 (HE) or low-dose E2 (LE) for 2 days. In addition, we used real-time PCR to study the effects of E2 on the expression levels of TRPV1 and ANO1 mRNA in trigeminal ganglia. In the behavioral experiment, the HE group showed significant potentiation of Cap-evoked nocifensive behavior compared with the LE group. Immunohistochemistry showed that Cap evoked a significantly greater number of cells that were immunoreactive for c-Fos, a marker of nociceptive activation, in the trigeminal subnucleus caudalis/upper cervical cord in the HE group than in the LE group. The number of c-Fos-immunoreactive cells in the ventral trigeminal interpolaris/caudalis were similar in the 2 groups. Real-time PCR showed that the levels of TRPV1 and ANO1 mRNA in the HE group were significantly higher than levels in the LE group. Thus, high levels of estrogens may be a risk factor for Cap-evoked nociceptive pain, and estrogen-dependent increases in TRPV1 and ANO1 are likely involved in modulating the nociceptive response in the trigeminal area.
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Kazuaki
K
Yamagata
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Mitsutaka
M
Sugimura
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Miki
M
Yoshida
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Shinichi
S
Sekine
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Akiyo
A
Kawano
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Aiko
A
Oyamaguchi
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Hiroharu
H
Maegawa
Department of Dental Anesthesiology (K.Y., M.Y., A.K., A.O., H.M., H.N.), Osaka University Graduate School of Dentistry, Suita City, Osaka, 565-0871 Japan; Department of Dental Anesthesiology (M.S.), Field of Oral Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima, Japan; and Division of Special Care Dentistry (S.S.), Osaka University Graduate School of Dentistry, Suita City, Osaka, Japan.
Hitoshi
H
Niwa
D000818:Animals; D000075369:Anoctamin-1; D002211:Capsaicin; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059226:Nociceptive Pain / Q000139:chemically induced* / Q000378:metabolism*; D010052:Ovariectomy; D017288:Pain Threshold; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism*
C552942:ANO1 protein, rat; D000075369:Anoctamin-1; D018118:Chloride Channels; D016760:Proto-Oncogene Proteins c-fos; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D004958:Estradiol; D002211:Capsaicin