Pannexin 1 channels and ATP signaling in mechanisms of peripheral pain sensitization

• Grant number: 19/15255-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: November 01, 2019
• End date: October 31, 2020
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Carlos Amilcar Parada
• Grantee: Júlia Borges Paes Lemes
• Supervisor: Sylvia Ottilie Suadicani
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Albert Einstein College of Medicine, United States
• Associated to the scholarship: 17/19105-8 - Study of the release of ATP in the dorsal root ganglion in the development of inflammatory hyperalgesia, BP.DR

Abstract

Under certain pathologic conditions as peripheral tissue injury, sensory pathway can be modified. In this case, pain signal is followed by a process named hyperalgesia. This phenomenon is a result of nociceptive fibers sensitization, which cause decrease of threshold neuronal excitability. This reduction is due to action of several mediators produced by inflammatory process. These mediators induce metabolic alterations on nociceptors that facilitate the production of action potentials from nociceptors. Among these mediators, we can find glutamate, substance P, cytokines and ATP. In recent years, extracellular ATP has emerged as a key player in a variety of diseases, including chronic and inflammatory pain. In addition, ATP has been shown to be a main mediator in the communication between neurons and satellite glial cells at sensory ganglia during pain transmission. Thus, identifying these molecules and their action mechanisms in the nervous system that result in inflammatory and chronic pain is essential to achieve the discovery of new therapeutic targets. In this context, the current PhD project of student Júlia Borges Paes Lemes reveal evidences that Pannexin1 (Panx1), ATP release channels, is important to pain transmission in peripheral inflammatory hyperalgesia. Thereby, the present project aims to investigate the role of these channels using sophisticated transgenic mice and new techniques applied to pain studies. The experiments will be performed at Albert Einstein College of Medicine in New York under the supervision of Dr. Sylvia Ottilie Suadicani. It will be used chemicals agents (Carrageenan and PGE2) injected in the hind paw of animals to induce inflammatory hyperalgesia, and Paclitaxel, component used as chemotherapeutic, to induce systemic neuropathic pain. Both pain models will be assessed by behavior testing in transgenic mice (Panx1-/-, Panx1+/+) and in mice with Panx1 knockdown in the dorsal root ganglia (DRG) using the Cas9-CRISPR system. Subsequently, Ca2+ imaging and dye-coupling (neuron-glia) with be performed in dorsal root ganglia cultures from these mice under different treatments to evaluate changes in intercellular signaling. (AU)