Role of succinate/GPR91 pathway in the development of paclitaxelinduced peripheral neuropathic pain

Author(s)

Francisco Isaac Fernandes Gomes

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-07-04

Examining board members

Thiago Mattar Cunha; Sandra Yasuyo Fukada Alves; Joice Maria da Cunha; Guilherme de Araujo Lucas

• Advisor: Thiago Mattar Cunha

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 paclitaxelinduced neuropathic pain is not fully elucidated. 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 and this metabolite can transduce signals through GPR91 activation. 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)

• FAPESP's process: 17/23815-0 - Involvement of the succinate receptor GPR91 in the genesis of neuropathic pain
• Grantee: Francisco Isaac Fernandes Gomes Aragão
• Support Opportunities: Scholarships in Brazil - Master