Estrogens Exacerbate Nociceptive Pain via Up-Regulation of TRPV1 and ANO1 in Trigeminal Primary Neurons of Female Rats

Abstract

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.

Chronic 17β-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats

“…By influencing the transcription of certain genes ( mitogen-activated protein kinase-1 , interleukin-1 receptor type I , bradykinin B2 receptor , GABA transporter protein , GABA A receptor subunit a6, opioid receptor-like 1 receptor , purinoreceptor P2X3 , transient receptor potential vanilloid 1 and neuropeptide Y ) with potential relevance to craniofacial pain, long-lasting changes were reported in different cells. 35 , 40 , 43 – 46 Estrogen can activate intracellular signaling pathways via non-genomic, membrane-mediated mechanisms also, which may occur within seconds or minutes. 40 , 47 – 50 These cellular mechanisms affect numerous processes, which are essential in trigeminal pain perception including the function of endogenous anti-nociceptive system, 51 , 52 the modulation of the excitability of TNC neurons.…”

“…The authors conclude that the effect may be in part due to the estrogen-dependent increases in mRNA of transient receptor potential vanilloid 1 and anoctamin 1 in TNC, which have important role in trigeminal pain. 46 …”

Sex-Dependent Effects of Cannabis and Cannabinoids: A Translational Perspective

“…Sixth, the major non-psychoactive component of cannabis, cannabidiol (CBD), is emerging as a cannabis constituent with potentially diverse therapeutic effects, but there are almost no sex comparisons of its effects, even in animals. Given the emerging evidence that TRPV1 channels-a major CBD target-are estradiol-modulated (Yamagata et al, 2016), examining sex differences in a variety of CBD effects is warranted.…”

TRP Channels as Potential Targets for Sex-Related Differences in Migraine Pain

“…When estrogen levels were monitored, either as a function of the estral cycle or its replacement after ovariectomy in rodents, it was observed that under low levels of 17β-estradiol, capsaicin produced a mild nocifensive response (Lu et al, 2009 ; Yamagata et al, 2016 ). In marked contrast, high levels of 17β-estradiol (proestrus) resulted in a lower mechano- and thermo-nociceptive threshold, thereby promoting mechanical and thermal sensitization (Payrits et al, 2017 ).…”

“…The molecular mechanisms involved in 17β-estradiol-induced sensitization of TRPV1 appeared to include both a genomic regulation of channel expression and a functional modulation. Regarding the long-term effect of estrogens in females, several studies showed a transcriptional-induced expression of TRPV1 by 17β-estradiol in nociceptors (Yamagata et al, 2016 ; Kumar et al, 2017 ; Payrits et al, 2017 ). Even sensory neurons derived from female mouse stem cells showed that the application of 17β-estradiol increased the expression of TRPV1 mRNA (Greaves et al, 2014 ).…”