Estrogens produced within the central amygdala inhibit varicella zoster-induced orofacial pain.

Abstract

Varicella zoster virus (VZV) causes chicken pox, and reactivation of this virus later in life causes shingles. Previous work demonstrated that estrogens could reduce VZV-induced orofacial pain and affect gene expression in the central amygdala. It is known that the central amygdala processes pain signals from the orofacial region and that estrogens produced by the enzyme aromatase within the central amygdala regulate neuronal function. Based on the previous studies, it was hypothesized estrogens produced within the central amygdala attenuate VZV-induced orofacial pain. To address this hypothesis, male Long-Evans rats were implanted with cannulas terminating in the central amygdala. Through these cannulas, the aromatase inhibitor letrozole or estrogen receptor alpha (ERα) agonist, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), was infused in the central amygdala. The whisker pad of each rat was injected with either MeWo cells or MeWo cells containing VZV. One week after VZV injection, letrozole or PPT was infused into the central amygdala, followed by measuring pain behavior, GABA release, and estradiol concentrations. Tissues in the orofacial pain pathway were isolated, and neuronal activity was quantitated by counting c-Fos-positive neurons. Letrozole significantly increased the pain response and decreased GABA release. Letrozole also decreased estradiol within the central amygdala. Infusion of PPT reduced pain and increased GABA release. Moreover, letrozole increased the number of active neurons in the lateral parabrachial nucleus and spinal trigeminal nucleus, while PPT reduced the number of active neurons in the trigeminal ganglia, lateral parabrachial nucleus, and spinal trigeminal nucleus. The results suggest aromatase-derived estradiol interacts with ERα within the central amygdala to attenuate VZV-induced pain by increasing GABA release and reducing neuronal activity in the pain pathway.