The role of indoleamine 2,3-dioxygenase in supraspinal structures in the induction and maintenance of neuropathic pain

• Grant number: 13/07968-0
• Support type: Scholarships in Brazil - Master
• Effective date (Start): August 01, 2013
• Effective date (End): January 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Dênis Augusto Santana Reis
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis, AP.TEM

Abstract

The mechanisms responsible for the induction and maintenance of neuropathic pain are not clear, it is believed that an inefficiency of descending inhibitory pain pathway could be one of the factors that would trigger, for example drugs that increase the levels of monoamines in this way are effective in overcoming pain. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the conversion of serotonin or tryptophan into biologically active metabolites through a biochemical pathway termed " kynurenine pathway ". Augmentation of IDO expression could lead to inefficiency of descending inhibitory pain pathway. We believe that the major metabolites of IDO pathway act as glutamatergic-like agonists, which may contribute to the induction and/or maintenance of the pathological state. Under non-pathological conditions IDO expression is low in different cells types, including macrophages, glial cells and neurons. However, in pathological situations, such as cancer and depression, it is observed an increased IDO expression. Recent results from our group showed that systemic treatment with an inhibitor of IDO virtually abolishes hypersensitivity to pain in an experimental model of neuropathy. Moreover, the injection of the inhibitor partially attenuates spinal hypersensitivity, suggesting that the IDO activity, other than spinal cord could contribute to maintenance of neuropathic pain. Additionally, IDO expression is increased in supraspinal structures during certain pathologies, including depression. Taking together, these results suggest that after peripheral nerve injury there is an increase in the activity and expression of IDO in the spinal cord and others supraspinal structures known to be involved in the pathophysiology of neuropathic pain (e.g. periaqueductal gray area and rostral ventromedial medulla). This particular phenomena would contribute to the genesis and/or maintenance of neuropathic pain by negative modulation of the descending inhibitory pain pathway. Therefore, the goal of the present project is to evaluate the contribution of IDO activation in supraspinal structures mentioned previously and its role in the maintenance of neuropathic mechanical hypersensitivity. Therefore, the outcome of the project could suggest a new therapeutic target for the treatment of neuropathic pain.

Academic Publications

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

REIS, Dênis Augusto Santana. Supraspinal kynurenine pathway contributes to the maintenance of neuropathic pain. 2015. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto Ribeirão Preto.