Neurotrophins action on the antinociceptive activity mediated by the monoaminergic system: integrating neurogenesis and neuropathic pain mechanisms

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: 1) investigate the influence of TrkB activity on the analgesic effect of serotonin reuptake inhibitors after peripheral nerve lesion. 2) explore the occurrence of neurogenesis in nociceptive associated nuclei as a consequence of peripheral nerve lesion, and the role of BDNF/NT-4 in this process. 3) the role played by BDNF and NT-4 in the proliferation and survival of newborn neurons induced by serotonin reuptake inhibitors under neuropathic pain conditions. 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. (AU)