Sex differences underlying orofacial varicella zoster associated pain in rats

Abstract

BackgroundMost people are initially infected with varicella zoster virus (VZV) at a young age and this infection results in chickenpox. VZV then becomes latent and reactivates later in life resulting in herpes zoster (HZ) or “shingles”. Often VZV infects neurons of the trigeminal ganglia to cause ocular problems, orofacial disease and occasionally a chronic pain condition termed post-herpetic neuralgia (PHN). To date, no model has been developed to study orofacial pain related to varicella zoster. Importantly, the incidence of zoster associated pain and PHN is known to be higher in women, although reasons for this sex difference remain unclear. Prior to this work, no animal model was available to study these sex-differences. Our goal was to develop an orofacial animal model for zoster associated pain which could be utilized to study the mechanisms contributing to this sex difference.MethodsTo develop this model VZV was injected into the whisker pad of rats resulting in IE62 protein expression in the trigeminal ganglia; IE62 is an immediate early gene in the VZV replication program.ResultsSimilar to PHN patients, rats showed retraction of neurites after VZV infection. Treatment of rats with gabapentin, an agent often used to combat PHN, ameliorated the pain response after whisker pad injection. Aversive behavior was significantly greater for up to 7 weeks in VZV injected rats over control inoculated rats. Sex differences were also seen such that ovariectomized and intact female rats given the lower dose of VZV showed a longer affective response than male rats. The phase of the estrous cycle also affected the aversive response suggesting a role for sex steroids in modulating VZV pain.ConclusionsThese results suggest that this rat model can be utilized to study the mechanisms of 1) orofacial zoster associated pain and 2) the sex differences underlying zoster associated pain.

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

“…The efficacy of this topical treatment suggests VZV pain involves peripheral neurites. Moreover, neurite retraction within the whisker pad and paw can be observed after VZV injection (Guedon et al, 2015 ; Stinson et al, 2017 ), consistent with humans that have VZV-induced neuralgia (Guedon et al, 2015 ). To address whether VZV-induced pain was due to damage at the peripheral nerve terminals, we injected VZV into the trigeminal ganglion.…”

“…Support for this idea comes from studies by the Kinchington lab demonstrating that expression of at least some viral proteins in the ganglia are necessary to induce the affective pain in animals (Guedon et al, 2014 ). For example, the VZV immediate early gene IE62 is present in humans with HZ and in VZV infected rat neurons (Kress and Fickenscher, 2001 ; Schaap-Nutt et al, 2006 ; Hama et al, 2010 ; Stinson et al, 2017 ). Dr. Kinchington (personal communication) has evidence that expression of this viral transcription factor alters neuronal function and that this factor is necessary for the pain response.…”

“…Because the magnitude of the behavioral response in the PEAP test has been shown to be greater than the thermal and mechanical response after VZV injection, all testing in this study was completed using the PEAP test (Stinson et al, 2017 ). Spontaneous behavioral responses were not significantly affected by VZV injection (Supplementary Figure S1).…”

“…Treatment of VZV infected animals with antivirals, opioids or NSAIDS is not highly effective, mirroring results in humans with pain after VZV infection (Rowbotham and Fields, 1996 ; Dalziel et al, 2004 ; Garry et al, 2005 ; Hasnie et al, 2007 ). Both sodium channel blockers and gabapentin can effectively treat VZV-induced pain in animals and humans (Garry et al, 2005 ; Hasnie et al, 2007 ; Rullán et al, 2017 ; Stinson et al, 2017 ). Thus, the rat model reflects aspects of the human disease and would provide information as to the mechanism by which VZV induces pain.…”

“…VZV injection of the whisker pad resulted in neurites to retract within the tissue (Stinson et al, 2017 ). This result is consistent with humans that have VZV-induced neuralgia (Guedon et al, 2015 ).…”