PKR-TRPV1 complex as a potential mediator of pathological pain: integrating modelling, signaling, and therapeutic value

• Grant number: 22/15306-7
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Agreement: University of Bath
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Guilherme de Araújo Lucas
• Principal researcher abroad: Carmen Domene
• Institution abroad: University of Bath, England
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 22/14342-0 - The effect of RNA-dependent protein kinase on TRPV1 activity in the antinociceptive mechanisms mediated by opioids, AP.R

Abstract

Our ability to sense heat, cold, touch or pain is essential for survival and underpins our interaction with the world around us. TRPV1 is the sensor that responds to heat and activates nerve cells causing pain sensations. How TRPV1 exerts this function is still an unsolved riddle. The processes of phosphorylation and dephosphorylation by kinases are crucial for TRPV1 function. Recent data show that, in addition to transduce noxious heat, TRPV1 paradoxically crosstalk with opioid receptor. Thus, the anti-nociceptive effect of morphine, the prototypical agonist of the 1/4-opioid receptor, and the most potent analgesic to treat patients with moderate to severe pain, is modulated by TRPV1 activity. However, 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. Thus, to avoid opioid side effects, the nociceptor where pain is generated should be targeted, and hence, there is a tremendous interest in the TRP family of ion channels. TRPV1 is subject of intensive drug discovery and development efforts, and our improved understanding of TRPV1-kinases interactions will undoubtedly contribute to aid drug discovery. Moreover, we have raised substantial evidence that PKR inhibition impaired morphine analgesia to heat noxious stimulation in mouse models of incisional and burning pain. This proposal combines computational chemistry with genetic, molecular and cellular methods as well as pharmacological and behavioral paradigms to uncover the PKR-TRPV1 interactions in the presence of drugs used to treat pathological pain. Interaction of PKR-TRPV1 and opioid analgesic 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. (AU)