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Involvement of the succinate receptor GPR91 in the genesis of neuropathic pain

Grant number: 17/23815-0
Support type:Scholarships in Brazil - Master
Effective date (Start): April 01, 2018
Effective date (End): June 30, 2019
Field of knowledge:Biological Sciences - Pharmacology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Thiago Mattar Cunha
Grantee:Francisco Isaac Fernandes Gomes
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Paclitaxel is a chemotherapeutic agent widely employed in the treatment of solid tumors, but the ensuing peripheral neuropathy is a dose-limiting side-effect and a common cause of treatment interruption. Paradoxically, neurons are susceptible to paclitaxel albeit they are not dividing cells. Axonal degeneration and demyelination correlate with clinical symptoms that persist well beyond treatment cessation. The pathogenesis of paclitaxel-induced neuropathic pain is not fully elucidated, and the inflammatory process can be considered a potential trigger. Additionally, paclitaxel-induced neuropathy can cause metabolic changes in the nociceptive system and the levels of citric acid cycle intermediates such as succinate can rise in such conditions. Succinate binds and transduces signals through GPR91 activation. Within the immune system, this receptor is expressed on dendritic cells and macrophages and, albeit the GPR91 role has been described in inflammatory conditions, e.g. rheumatoid arthritis, its involvement in neuropathic processes is unknown. Preliminary results from our group show that GPR91-/- mice are less prone to develop mechanical and thermal hypersensitivity during paclitaxel-induced peripheral neuropathy. Knowing such information, this research project aims to evaluate the mechanisms through which GPR91 is involved in the development of paclitaxel-induced neuropathic pain by using pharmacological and genetic tools in experimental murine models. Clarifying the functional role of this receptor would add an unprecedented concept in the chronic pain field of study, suggesting a novel therapeutic target for studies on analgesia. (AU)

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