The role of pattern recognition receptors like toll-like receptors 4 in the induction and maintenance of herpetic and post-herpetic neuralgia

• Grant number: 14/09008-7
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2014
• Effective date (End): March 31, 2016
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal researcher: Thiago Mattar Cunha
• Grantee: Cássia Regina da Silva
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis, AP.TEM

Abstract

Herpetic neuralgia (HN) is characterized by a painful vesicular rash resulting from Varicella-Zoster virus (VZV) reactivation in the dorsal root ganglia (DRGs) or cranial nerves, decades after primary infection with varicella. However, even after the rash resolution, pain may persist for months or even years, defining the post-herpetic neuralgia (PHN). The VZV specifically infects humans. Accordingly, the herpes simplex virus type-1 (HSV-1), which is able to equally infect humans and rodents, is used as the animal model of HN and PHN. Both, VZV and HSV-1, access the sensory neurons through axon terminals and reach the dorsal root ganglia (DRGs). It is believed that pain during HN and PHN is due to the release of inflammatory mediators on the DRGs, as a result from glial cells activation, cells from the immune response which infiltrate the DRGs or sensory neurons sensitization. Both satellite cells and cells derived from immune system activation are able to release different danger-associated molecular patterns such as the MRP14 protein. MRP14 is a Toll-like receptor 4 (TLR4) agonist, and TLR4 activation by MRP14 leads to the release of inflammatory mediators. Furthermore, TLR4 is involved in hipernociception induction during neuropathic pain models resulting from mechanical nerve injury. However, there is no data about TLR4 and MRP14 involvement in HN and PHN, or about the mechanisms involved on the initiation of these neuralgias. Thus, the aim of this study is to verify if during HSV-1 infection there is MRP14 release and consequent TLR4 activation on DRGs sensory neurons, resulting in the release of inflammatory mediators involved in HN and PHN.