Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus

Abstract

Pain is a common complication of herpes zoster (HZ) infection which results from reactivation of a latent varicella zoster virus (VZV). A third of HZ patients’ progress to a chronic pain state known as post herpetic neuralgia (PHN), and about a quarter of these patients’ have orofacial pain. The mechanisms controlling the pain responses are not understood. Studies suggest central pathways involving the thalamus could control pain related to HZ, and studies in our lab suggest vesicular GABA transporter (VGAT) in the lateral thalamus influences orofacial pain. We hypothesized that thalamic VGAT functions, in part, to reduce pain, particularly orofacial pain, associated with VZV. To address this hypothesis VZV was injected into the whisker pad. Affective and motivational aspects of pain were measured using the Place Escape/Avoidance Paradigm. Thalamic neuronal activity was modulated after injecting an adeno-associated virus (AAV) expressing an engineered acetylcholine Gi-protein coupled receptor. This receptor inhibits neuronal firing when bound by clozapine-n-oxide (CNO). VGAT expression was attenuated in the thalamus by injecting an AAV construct that expressed a VGAT silencing shRNA. VZV induced nociception was significantly decreased after administering CNO in male rats. Nociception significantly increased concomitant with increased thalamic c-fos expression after attenuating thalamic VGAT expression. These data establish that the lateral thalamus (posterior, ventral posteromedial, ventral posterolateral and/or reticular thalamic nucleus) controls VZV induced nociception in the orofacial region, and that GABA in this region appears to reduce the response to VZV induced nociception possibly by gating facial pain input.

Role for the Ventral Posterior Medial/Posterior Lateral Thalamus and Anterior Cingulate Cortex in Affective/Motivation Pain Induced by Varicella Zoster Virus

“…The virally infused construct expressed an engineered acetylcholine Gi receptor that upon activation with CNO will act as a neuronal silencer. CNO administration significantly decreased the behavioral response in weeks 1 (Figure 2A ), 2 (Figure 2B ) and 3 (Figure 2C ) consistent with previous results (Kramer et al, 2017 ).…”

“…After infusion the needle was left in place for 5 min and then removed. Using these coordinates and injection procedure the modified acetylcholine Gi protein-coupled receptor was expressed primarily in the VPM, VPL with a smaller amount of expression in the reticular (Rt) thalamic nuclei, as well as, the zona incerta (ZI) of Sprague-Dawley rats (Kramer et al, 2017 ).…”

“…Previous work in our laboratory suggested that a central mechanism was involved, specifically that GABA within the ventral posterior medial/posterior lateral thalamus (VPM/VPL) modulated VZV-induced nociception (Kramer et al, 2017 ). The question remained as to what role specific cellular populations within the lateral thalamus had in VZV-induced pain.…”

Aromatase Derived Estradiol Within the Thalamus Modulates Pain Induced by Varicella Zoster Virus

“…After infusion, the injector cannula was left in place for 5 min, removed and the obturator replaced. Previous reports demonstrate that 500 nanoliters injected at these coordinates spreads to the posterior thalamic nucleus (Po), ventral posteromedial (VPM) and ventral posterolateral thalamic nuclei (VPL) and the Rt (Kramer et al, 2017 ).…”

Modeling Varicella Zoster Virus Persistence and Reactivation – Closer to Resolving a Perplexing Persistent State

“…The maintenance of viral DNA in rat ganglia is consistent with VZV entry into rat cells (and neuronal axons) without need for complete replication (Guedon et al, 2015). It will be interesting to determine if VLT is made in rat models, particularly since Wistar and Sprague Dawley rats develop prolonged behavioral signs of VZV-induced mechanical hypersensitivity (Fleetwood-Walker et al, 1999; Dalziel et al, 2004; Garry et al, 2005; Hasnie et al, 2007; Guedon et al, 2014, 2015; Kramer et al, 2017; Stinson et al, 2017).…”