On the role of RNA dependent protein kinase in the analgesic effect of opioids in a murine model of incisional and burning pain.

• Grant number: 23/00298-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2023
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Paulo Bogdan Sanson
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Analgesic drugs that act through opioid receptors represent the main analgesic option for severe pain caused cancer, burning, post-surgical pain or urolithiasis. However, the pharmacological control of chronic pain is frequently unsatisfactory and the long-term use of opioids, such as morphine, often causes tolerance, physical dependence, and respiratory depression. Recently, we found robust evidence that the inhibition of RNA-dependent protein-kinase (PKR), significantly hampered the analgesic effect of morphine in a mouse model of incisional pain. This proposal combines molecular and cellular methods as well as pharmacological and behavioral paradigms to uncover the PKR-opioid receptor interactions in mouse models of incisional and burning pain. It will be investigated the effect of PKR inhibition on the antinociceptive effect of morphine, as well as the development of analgesic tolerance and physical dependence. In addition, it will be monitored the phosphorylation status of PKR and its endogenous activator RAX in the dorsal root ganglion and in the spinal cord dorsal horn following acute and chronic administration of morphine. The effect of PKR on the analgesic effect of opioid drugs offers a completely new view to the mechanisms of action of these drugs and should lead to a better understanding of the fundamental biology of chronic pain. Most importantly, the overall goal of these studies may reveal novel targets for development of more effective analgesic drugs.