The Role of P2X4 receptors of the dorsal root ganglia in the development of chronic hyperalgesia

• Grant number: 16/23535-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2017
• Effective date (End): November 30, 2019
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Carlos Amilcar Parada
• Grantee: Glaucilene Ferreira Catroli
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 18/05778-3 - The role of purinergic receptor P2X4 signaling of dorsal root ganglia and spinal cord in early and late phase allodynia in the K/BxN mouse model of chronic inflammation., BE.EP.DR

Abstract

The mechanisms involved in the origin of neuropathic hyperalgesia are still a great challenge to the development of drugs that efficiently and selectively control pain of neuropathic origin. Although neuropathy can be both related to different causes and systemic diseases, all of them depend on the sensitization of nociceptors, which are associated with C-fibers and with myelinated A´ fibers. Differently, the mechanism of inflammatory hyperalgesia involves almost exclusively the C-fibers. P2X-type purinergic receptors, which are activated by extracellular ATP, either can act directly on nociceptors, activating and sensitizing them, or indirectly, leading to the release of inflammatory mediators that, in turn, are able to sensitize nociceptors. This is the case of the receptors P2X2, 2/3 and P2X7, which are essentials for the inflammatory hyperalgesia development. Recently, the interest on purinergic signaling has been focused on receptors of the P2X4 subtype which has the same functional characteristics as the P2X7 one. Although both of them are in the satellite glial cells of dorsal root ganglia, it has been shown by our group that, by blocking the P2X7 receptor, but not P2X4, the inflammatory hyperalgesia of the peripheral tissue is prevented. On the other hand, the blockage of the receptor P2X4 reduces the hyperalgesia in a model of rats with diabetic neuropathy. Considering that the inflammatory hyperalgesia studied was an acute form and that hyperalgesia in a rat model with diabetic neuropathy is a chronic form, these preliminary data point us to an important question: is the activity of P2X4 receptor in the development of hyperalgesia of neuropathic origin related to the fact that it is a persistent hyperalgesia? In other words, is it a receptor that is functional only after plastic changes occur in the DRG cells? The answer to this question and a better comprehension of the mechanisms involved in the hyperalgesia mediated by P2X4 activation in DRG, will bring us important knowledge to understand better the pathophysiology of neuropathic and/or chronic pain. Besides this, the fact that the P2X4 receptor is found in the peripheral nervous system makes it one of the most promising pharmacological targets for the control of neuropathic pain. Therefore, the purposes of this study are: verify the involvement of DRG P2X4 receptor in acute and persistent hyperalgesia of neuropathic and inflammatory origin; study the mediators released by the P2X4 activation that can, after all, sensitize the nociceptors. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

CATROLI, Glaucilene Ferreira. The role of P2X4 receptors of the dorsal root ganglia in the development of chronic hyperalgesia. 2020. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.