On the role of RNA dependent protein kinase in opioid-induced hyperalgesia in a experimental model of chronic pain.

• Grant number: 23/15478-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2024
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Lucas Fogagnoli de Carvalho
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Opioids are the main analgesic for severe pain such as cancer pain, burning and post-surgery pain. However, the use of opioids such as morphine is often associated with side effects such as tolerance, dependence, respiratory depression and, paradoxically, hyperalgesia. In this project we will investigate some of the putative intracellular mechanisms related to opioid-induced hyperalgesia.Preliminary data from our laboratory have shown that RNA-dependent protein kinase (PKR) plays an important role in the nociceptive system, facilitating heat pain transmission during peripheral inflammatory circumstances, likely via interaction with TRPV1. On the other hand, we raised substantial data showing that PKR influences the analgesic effect of opioid under pathological pain conditions. However, low doses of morphine cause hyperalgesia in the absence of peripheral lesion, and analgesia in the presence of peripheral inflammation. This suggested that opioid receptor may signal through different pathways, depending on the dose of opioid and the structural conformation of the receptor. Therefore, the phosphorylation status of de MAPKs (ERK1,2, p38 e JNK) as well as PKR and PACT/RAX will be monitored in the dorsal root ganglion neurons of naïve and lesioned mice by plantar incision in the left paw. Moreover, the effect of pharmacological inhibition of PKR on the phosphorylation status of MAPKs following low dose of morphine administration will also be investigated. Thus, we will combine molecular and cellular methods with pharmacological and behavioral paradigms in order to reveal the mechanisms underlying PKR action on different intracellular signaling pathways following µ opioid receptor activation by doses that causes analgesia and hyperalgesia. The results of the project must show new mechanisms of opioids action in the nociceptive system and the development of more efficient therapeutic strategies.