Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain

Abstract

Opioides have an addictive effect generate tolerance upon prolonged use causing unwanted side effects. Thus, there is a great need to search for new analgesic substitutes. To this end, understanding the signaling pathways that lead to pain can help develop new non-opioid analgesics. Inflammatory pain begins with the secretion of nerve growth factor (NGF) and activation of its high affinity receptor, Tropomyosine kinase A (TrkA) in sensory peripheral neurons. Through neuronal depolarization this signal is transmitted to the central nervous system (CNS). Due to the fact that TrkA is also a key kinase involved in the development of the sensory nervous system several mutations lead to Congenital Insensitivity to Pain with Anhidrosis (CIPA), which is the lack of nociceptive pain. Chronic pain involves Long-term potentiation (LTP), that is the strengthening and formation of more durable synapses, a process also important for memory and learning. This process leads to remodeling of the brain mainly of the anterior cingulate cortex (ACC) in the case of chronic pain. One of the key kinases involved in the establishment of LTP is Protein kinase C Mzzeta (PKMz). However, the specific role of this kinase in LTP has still not been elucidated. New strategies for the development of new analgesics have TrkA as a target of the peripheral nervous system and at the central level inhibition of remodeling is desirable. Thus, in the present project we aim at studying signaling pathways involved in the transmission of signals of inflammatory nociceptive pain by NGF and TrkA and at the central level pathways that lead to the establishment of LTP, and chronic pain mediated by PKMz. To this end, we will study TrkA, mutations found in patients with CIPA, mapping molecular changes caused by the mutations in pain signal transduction pathways, and in the development of the sensory nervous system (using chicken embryos). We will identify and characterize new pharmacological modulators of the activity of TrkA that have an effect on inflammatory pain. We will determine the epigenetic factors and signaling pathways that modulate the expression of PKMzz and how these factors influence the expression of the kinase in chronic pain. We will identify PKMz substrates and binding proteins validating their role in brain remodeling and chronic pain. (AU)