Abstract

Pain, as the most prevalent neurological complication of herpes zoster (HZ), may occur before or during the rash onset or even after the rash has recovered. Particularly, postherpetic neuralgia (PHN) is a refractory chronic condition, usually defined as pain persisting for 3 months or longer from the onset of HZ. Pain evoked by HZ impairs the normal physical and emotional functions of the patients, severely reducing their quality of life. However, how zoster-associated pain occurs and develops into PHN are elusive, making PHN difficult to predict. Uncovering the pathogenesis of zoster-associated pain (or HN) helps us to better understand the onset of PHN and supports developing more effective treatments. In this study, we successfully constructed a model for zoster-associated pain through varicella-zoster virus (VZV) infections of mouse footpads and pain behavior assessments. Next, we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO) to analyze PHN rodent dorsal root ganglion (DRG) gene microarray data and found that calcium signal disorder might be involved in the onset of PHN. By using reverse transcription real-time fluorescent quantitative PCR (RT-qPCR) and Western blotting, we confirmed that VZV infection could significantly upregulate the expression of T-type calcium channel Cav3.2 in DRG and spinal dorsal horn (SDH). Intrathecal administration of Cav3.2 blocker (2R/S)-6-prenylnaringenin (6-PNG) relieved mechanical and thermal hyperalgesia induced by VZV. Taken together, our data indicated that VZV might participate in the occurrence and development of HN by upregulating the expression of Cav3.2 in DRG and SDH. These findings will help to reveal the underlying mechanisms on long-lasting pain and PHN formation, providing a new insight that Cav3.2 can be the promising drug target for remitting PHN.

Highlights

  • Herpes zoster (HZ) episodes, after the reactivation of latent varicella-zoster virus (VZV) in the sensory ganglia, are accompanied by rash and severe acute pain [1]

  • The allodynia continued until day 63 (Figures 1B,C), mimicking the chronic condition of long-lasting neuralgia that may further form postherpetic neuralgia (PHN)

  • Compared with the control group, the results of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO) analysis showed that the biological functions of the differentially expressed genes (DEGs) in PHN rodent dorsal root ganglion (DRG) are mainly involved in the calcium signal pathways

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Summary

Introduction

Herpes zoster (HZ) episodes, after the reactivation of latent varicella-zoster virus (VZV) in the sensory ganglia, are accompanied by rash and severe acute pain [1]. Some still experience chronic pain and 9–14% of patients develop postherpetic neuralgia (PHN) suffering from refractory pain sensation for months or even years after the skin lesion heals [4]. This may lead to disparate secondary consequences that affect the quality of life, causing depression, withdrawal from society, and even suicide [5, 6]. It is urgent to elucidate the pathogenesis of zoster-associated pain and the development of PHN. Better understanding of HN will help to identify meaningful targets and develop new treatments

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