Role of succinate/GPR91 signaling in the physiopathology of neuropathic pain

• Grant number: 12/23846-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2013
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Ricardo Kusuda
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 16/17029-0 - Study of succinate effect on sensory neurons: skin-nerve preparation, patch clamping, calcium imaging and CGRP release approaches, BE.EP.PD

Abstract

Nowadays, chronic pain is one of the most important health problems. Trials are hardly handled trying to elucidate tissue, cellular and molecular events responsible for triggering this illness. This could make a difference for efficient treatments needed. Succinate is a product of GABA metabolization, a compound of Krebs' circle and a GPR91 ligand. GPR91 was considered as an orphan receptor from G protein receptors family, and its expression was found in neurons and dendritic cells. Besides, acts synergically with Toll-like receptors and triggers Ca2+ currents in glial cells. Peripheral nerve injury causes gabaergic neuron degeneration in spinal cord and promotes cell stress increasing local metabolism, what ends in metabolite accumulation. Preliminary results of our group show that succinate, intrathecally injected, is responsible for the induction of mechanical allodynia in naïve mice early 1 hour post-injection. Others findings show that GPR91 knockout mice develop less hypersensitivity to the mechanical stimulus 14, 21 and 26 days post-injury comparing to their wild type littermates. With this information and evidences on hands, by current methodological paradigms that integrate cellular and molecular biology, behavior, pharmacology and genetics tools, here we are proposing to test the hypothesis that succinate has a major pronociceptive role, via GPR91 activation, in mice nociceptive system under neuropathic pain elicited by peripheral nerve injury. The possibility of having this proof would sum an important and inedited concept to the chronic pain field, suggesting a new target for efficient analgesic therapies.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

KUSUDA, RICARDO; CARREIRA, ELEONORA UCHOA; ULLOA, LUIS; CUNHA, FERNANDO QUEIROZ; KANASHIRO, ALEXANDRE; CUNHA, THIAGO MATTAR. Choline attenuates inflammatory hyperalgesia activating nitric oxide/cGMP/ATP-sensitive potassium channels pathway. Brain Research, v. 1727, JAN 15 2020. (12/23846-0, 13/08216-2, 11/20343-4, 10/16823-8)