Estradiol and Zoster Associated Orofacial Pain
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abstract
People with herpes zoster (HZ) or “shingles†can suffer from orofacial pain. Orofacial HZ is caused by thereactivation of latent varicella zoster virus (VZV) in the trigeminal ganglia. Importantly, women report HZ painthree times more often than men, but the mechanism for this sex disparity is unknown. A screen by our lab ofover 20,000 genes in five different regions of the orofacial pain pathway revealed that the greatest change ingene expression occurred in the thalamus, such that glutamate decarboxylase 2 (GAD2) and vesicular GABAtransporter (VGAT) were elevated at proestrus (high 17 β-estradiol, E2) but not diestrus (low E2). Inpreliminary studies we showed that female rats have a greater VZV induced orofacial nociceptive response incomparison to males; mirroring the human sex difference. We also showed that reducing E2 production inmale and female rats increases their nociceptive response and lastly, knock-down of VGAT expression in thethalamus increased the nociceptive response. Based on these studies we hypothesized that E2 attenuatesorofacial nociception by increasing GAD2 or VGAT, enhancing GABAergic neural inhibition within thethalamus to reduce pain. To test this hypothesis, Aim 1 will characterize thalamic control of the VZV inducedorofacial nociceptive response. The working hypothesis for Aim 1 is that GABA interneurons inhibit neuronsin the thalamus to reduce VZV induced nociception. To test this hypothesis first, VZV induced nociceptionand neuronal activity will be recorded after attenuating inhibitory interneurons. Second, nociception andneuronal activity will be determined after modulating GAD2 and VGAT expression in these interneurons. Aim2 will determine the role of sex steroids in modulating the VZV induced nociceptive response. Our workinghypothesis is that E2 will increase expression of VGAT and GAD2 in the thalamus causing attenuation ofneuronal activity and the nociceptive response. To test this hypothesis first, the nociceptive response andneuronal 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 expressionin rats with varied E2 levels. Aim 3 will characterize the mechanism by which sex steroids modulate VGATand GAD2 to affect the VZV induced orofacial nociceptive response. Our working hypothesis is that E2 bindsto estrogen receptor alpha (ERα) causing increased expression of VGAT and GAD2 in the thalamus resultingin attenuation of nociception. To test this idea, the nociceptive response and neuronal activity will bequantitated in rats after mutating ERα promoter sites using CRISPR/Cas9 technology. From these three aimswe expect to determine 1) that GABA interneurons inhibit thalamic signaling to reduce orofacial pain, 2) thatGAD2 and VGAT increases in these neurons through an ERα dependent mechanism, and 3) that GAD2 andVGAT are responsible, in part, for the sex difference observed in HZ pain. Identifying a mechanism by whichE2 affects HZ-associated pain will provide new targets for treating people suffering from this chronic disorder.
