The effect of RNA-dependent protein kinase on the analgesic effect of cannabinoid during chronic inflammatory pain.

• Grant number: 23/01401-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2023
• End date: April 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Thiago Pimenta Santos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

RNA-dependent protein kinase (PKR) is a serine/threonine kinase known as a 'sentinel' molecule due to its role in monitoring extracellular factors that threats cellular physiology. PKR activation represents the initial steps of cellular adaptation after pathogen invasion or any other stimulus that causes adaptative changes to a new cellular environment. In addition to the action of double stranded RNA produced by viruses, PKR is also phosphorylated by inflammatory mediators, growth factors, cytokines, and oxidative stress. Therefore, PKR activity play an important role in cell differentiation, transcription, apoptosis, and cellular growth. Our preliminary data shows that also PKR mediates thermal hyperalgesia in murine models of inflammatory pain, likely by acting on TRPV1 channels. In this project, we will investigate putative mechanisms related to the antinociceptive effect mediated by CB2 cannabinoid receptors its effect on the thermal hyperalgesia caused by two models of chronic pain: the incisional model and the burning model. These models show different TRPV1 response to the peripheral stimulus and we will investigate whether PKR activity modulates the analgesic effect of CB2 receptor activity. Our main goals are: (a) to investigate the effect of a CB2 agonist on thermal hyperalgesia caused by peripheral incisional and thermal lesion in C57Bl/6; (b) to investigate the effect of PKR inhibition on the anti-thermal hyperalgesia induced by CB2 agonist; (c) to monitor the effect of CB2 agonist on the expression profile of PKR, RAX, TRBP and their phosphorylated forms in the dorsal root ganglion and the spinal cord dorsal horn ipsilateral to the lesion; (d) to monitor the expression of CB2 receptor in the mouse dorsal root ganglion and the spinal cord dorsal horn during peripheral inflammation caused by plantar incision or burning.This project combines cell biology methods with pharmacological and behavioral paradigms in order to explore potential interactions between CB2, PKR and TRPV1 in animals models of inflammatory pain. The effect of PKR-TRPV1 interaction on the analgesic mechanisms induced by cannabinoid CB2 receptor represents a completely new view of the mechanisms of analgesic drugs and can provide a better understanding of the fundamental neurobiology of chronic pain. Most importantly, our results may reveal new therapeutic targets for the development of more effective therapies for severe chronic pain.