Action of monoamines on TrkB receptor activity for neutrophins in dorsal spinal cord in a peripheral neuropathy experimental model

• Grant number: 06/05471-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2007
• End date: July 31, 2009
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Adriano Cardozo Franciosi
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Neuropathic pain is an intractable, chronic syndrome that may arise from injury to peripheral nerves and is associated with allodynia, hyperalgesia, spontaneous pain, repetitive discharge of nociceptors and the expansion of receptive fields of nociceptive input. Our understanding of the pathophysiology of this debilitating syndrome is very limited and represents the main obstacle to the development of more effective therapeutic strategies. Recently, in vitro studies indicate that TrkB neurotrophin receptor strongly modulate serotoninergic activity, suggesting a communication between two different classes of receptors. In the present study, we will explore the functional consequences of this interaction in an animal model of neuropathic pain. The main objectives of the project are: (a) to investigate in the spinal cord dorsal horn the phosphorylation status of Y490 (Shc binding site), Y674/675 (autophosphorylation site), and Y785 (PLCgamma-1 binding site) on TrkB neurotrophin receptor following peripheral nerve injury; (b) the efect of acute and chronic administration of serotonin/noradrenaline reuptake inhibitors on Trk-B activation after peripheral nerve injury. This proposal combines unique genetic tools, molecular and cellular methods with pharmacological and behavioral paradigms to uncover the contribution of neurotrophic factors in the action of serotoninergic activity. We will pursue multidisciplinary studies aiming at delineating new, fundamental neurobiological mechanisms underlying chronic pain. Most important, this project may reveal novel mechanistically based targets for development of more effective and specific analgesic drugs.