Project Details
Projekt
Molecular and cellular functions of Trk receptors in axonal induction and resolution of nociceptor excitability
Applicants
Dr. Michael Briese; Professor Dr. Michael A. Sendtner
Subject Area
Molecular and Cellular Neurology and Neuropathology
Anaesthesiology
Anaesthesiology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Signaling mechanisms for enhanced transduction of nociceptive stimuli are key to understanding the cellular basis of pain persistence and resolution. Nerve growth factor (NGF) and other members of the neurotrophin family are well-known for their role in promoting neuronal survival and modulating function of nociceptors and other types of sensory neurons. NGF can induce long-lasting pain through upregulation of brain-derived-neurotrophic factor (BDNF) expression that acts both on postsynaptic neurons in the spinal cord as well as in an auto-paracrine manner on presynaptic TrkB receptors on nociceptive neurons. The mechanisms that then lead to pain persistence or resolution are not fully understood, but multiple lines of evidence suggest that altered gene expression, altered subcellular transport of specific mRNAs, and altered translational control in axons of nociceptors contribute to chronic pain. In this project, we would like to follow the hypothesis that neurotrophins potentiate axonal translocation of specific mRNAs and also regulate the local presynaptic translation of these transcripts for the induction of long-term changes at presynaptic sites that lead to enhanced excitability and synaptic activity of nociceptive sensory neurons and thus to pain chronification. Pain resolution depends on the reversion of these mechanisms. Using compartmentalized cultures of nociceptive sensory neurons, we would like to investigate changes in the axonal transcriptomes of nociceptors that occur when axons are locally exposed to NGF, and identify alterations both in general transcript levels and, in particular, in transcripts for which the translocation to axonal compartments is specifically enhanced. We also hypothesize that elevated TrkB and BDNF expression and release of this neurotrophic factor from presynaptic terminals of nociceptors induces autocrine presynaptic activation of TrkB, which then induces longterm changes in local protein synthesis in chronic pain. These results could be a basis for development of new strategies for pain resolution, based on strategies that abolish TrkB responsiveness at these synaptic sites.
DFG Programme
Clinical Research Units
