Estradiol Controls Varicella Zoster Virus Associated Nociception through Gabaergic Thalamic Signaling Mechanism
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Post-Herpetic Neuralgia (PHN), a chronic pain condition resulting from Herpes Zoster (HZ), is reported by females 3.75 times more often than men. Investigating the role of estradiol in thalamic gene expression, neuronal activity in the ventral posteromedial thalamus (VPM) and the Varicella Zoster Virus (VZV) associated pain response, can contribute to identifying mechanisms in which estradiol modulates the orofacial nociceptive processes of PHN and contributes to this disparity. VZV was injected into the whisker pad of adult Sprague Dawley rats. Changes in orofacial nociception and the affective nociceptive response, i.e. place escape avoidance paradigm (PEAP) were measured. Local field potentials (LFPs) of the VPM were recorded simultaneously while inhibiting neuronal activity to investigate its effects on the VZV associated nociception response. Gene expression changes in cycling SD rats was analyzed by RT-PCR. Plasma estradiol levels were measured at different phases of the estrous cycle to monitor changes in thalamic gene expression during periods of low and high estradiol and identify key genes that modulate VZV associated nociception through estradiol induced changes in thalamic gene expression. Vesicular GABA Transporter (VGAT) expression was attenuated in the thalamus by injecting a VGAT silencing shRNA and the VZV associated nociception response was measured in both male and female rats. As seen in human PHN, infected rats showed neurite retraction in the whisker pad, translocation of VZV to neurons in the trigeminal ganglia (as evident by IE62 staining) and gabapentin amelioration of the nociceptive response. Increases in thermal hyperalgesia, mechanical allodynia and PEAP were observed. Female rats showed a longer VZV associated affective response than males and when plasma estradiol concentrations were decreased, the affective response to VZV injection increased. In ovariectomized rats with hormone replacement, estradiol levels mirroring the proestrus phase of the natural cycle, reduced VZV associated nociception. The expression of VGAT was significantly increased in the lateral thalamus during the high estrogen phases (proestrus and estrus) of the estrus cycle. After VGAT silencing in the lateral thalamus, VZV associated nociception significantly increased in both male and female rats. Altogether exhibiting that estradiol controls VZV associated pain through VGAT GABAergic thalamic signaling.
Stinson, Crystal Pearl (2017). Estradiol Controls Varicella Zoster Virus Associated Nociception through Gabaergic Thalamic Signaling Mechanism. Doctoral dissertation, Texas A & M University. Available electronically from