# Estradiol and Zoster Associated Orofacial Pain

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $355,064

## Abstract

ABSTRACT
People with herpes zoster (HZ) or “shingles” can suffer from orofacial pain. Orofacial HZ is caused by the
reactivation of latent varicella zoster virus (VZV) in the trigeminal ganglia. Importantly, women report HZ pain
three times more often than men, but the mechanism for this sex disparity is unknown. A screen by our lab of
over 20,000 genes in five different regions of the orofacial pain pathway revealed that the greatest change in
gene expression occurred in the thalamus, such that glutamate decarboxylase 2 (GAD2) and vesicular GABA
transporter (VGAT) were elevated at proestrus (high 17 β-estradiol, E2) but not diestrus (low E2). In
preliminary studies we showed that female rats have a greater VZV induced orofacial nociceptive response in
comparison to males; mirroring the human sex difference. We also showed that reducing E2 production in
male and female rats increases their nociceptive response and lastly, knock-down of VGAT expression in the
thalamus increased the nociceptive response. Based on these studies we hypothesized that E2 attenuates
orofacial nociception by increasing GAD2 or VGAT, enhancing GABAergic neural inhibition within the
thalamus to reduce pain. To test this hypothesis, Aim 1 will characterize thalamic control of the VZV induced
orofacial nociceptive response. The working hypothesis for Aim 1 is that GABA interneurons inhibit neurons
in the thalamus to reduce VZV induced nociception. To test this hypothesis first, VZV induced nociception
and neuronal activity will be recorded after attenuating inhibitory interneurons. Second, nociception and
neuronal activity will be determined after modulating GAD2 and VGAT expression in these interneurons. Aim
2 will determine the role of sex steroids in modulating the VZV induced nociceptive response. Our working
hypothesis is that E2 will increase expression of VGAT and GAD2 in the thalamus causing attenuation of
neuronal activity and the nociceptive response. To test this hypothesis first, the nociceptive response and
neuronal activity will be measured in female and male rats after administering E2 or reducing E2 production.
Second, nociception and neuronal activity will be measured after knock-down of GAD2 and VGAT expression
in rats with varied E2 levels. Aim 3 will characterize the mechanism by which sex steroids modulate VGAT
and GAD2 to affect the VZV induced orofacial nociceptive response. Our working hypothesis is that E2 binds
to estrogen receptor alpha (ERα) causing increased expression of VGAT and GAD2 in the thalamus resulting
in attenuation of nociception. To test this idea, the nociceptive response and neuronal activity will be
quantitated in rats after mutating ERα promoter sites using CRISPR/Cas9 technology. From these three aims
we expect to determine 1) that GABA interneurons inhibit thalamic signaling to reduce orofacial pain, 2) that
GAD2 and VGAT increases in these neurons through an ERα dependent mechanism, and 3) that GAD2 and
VGAT are responsible, in...

## Key facts

- **NIH application ID:** 9905497
- **Project number:** 5R01DE026749-03
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** PHILLIP R KRAMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,064
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905497

## Citation

> US National Institutes of Health, RePORTER application 9905497, Estradiol and Zoster Associated Orofacial Pain (5R01DE026749-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905497. Licensed CC0.

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