Neurotrophic factors and pain states in neurons

Neurotrophins and mRNA

Does chronic pain alter gene activity and gene-dependent synthesis of proteins in the axon of a pain conducting nerve fibre? In neuropathies, that means painful nerve inflammations, the function of these sensory nerve cells is altered via neurotrophic factors such as Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF), so that pain can become chronic. Both factors are neurotrophins, stimulating the growth and connectivity of nerve cells. They bind to so-called tyrosine kinase receptors (Trk receptors) on the membrane surface of the nerve cell and thereby exert their effects.

However, their short- or long-term action on the nerve cell may lead to a change in mRNA distribution in nerve cell processes. Consequently, the synthesis of proteins in axons and synaptic compartments – the cell regions that are crucial for stimulus triggering – might be altered, which in turn would influence the excitability and signal transmission to other nerve cells. 

Research Goal

Project 8 of ResolvePain will investigate how the actions of neurotrophins affect local protein synthesis leading to altered excitability and pain chronification. 

Preclinical studies

Newly developed neuronal cell culture techniques are used to analyse the transcriptomes of the somatic and axonal regions of nociceptive neurons. This is performed using microfluidic chambers, which allow the outgrowth of nerve cell processes into a separate part of the cell culture chamber. The molecules identified from this will be investigated with regard to their function in pain excitation in further experiments in tissue samples from patients and their significance in pain recovery patterns will be analysed. 

Clinical study

In parallel, effects of neurotrophins in samples from patients with complex regional pain syndrome or polyneuropathies will be studied, which often occur as side effects of the chemotherapeutic drug bortezomib, and their significance in pain resolution will be determined. 

Modern techniques 

In cooperation with the University of Leipzig, a high-resolution microscopy technique is used to also visualize structural changes in the cells of the dorsal root ganglia. 

In addition, P8 provides technical support to other projects, such as techniques for neuronal cell culture based on human stem cells, or laser-assisted qPCR from tissue sections.

Importance 

Knowledge of local protein synthesis mechanisms in pain generation and resolution is still limited. In particular, insights into the molecular and cellular functions of Trk receptors under the influence of neurotrophins in the axon of a pain receptor could open new paths in pain therapy. 

Research Team P8

Head

Univ.-Prof. Dr. Michael Sendtner, MD
Institute of Clinical Neurobiology
University Hospital Würzburg

PD Dr. rer. nat. Michael Briese
Institute of Clinical Neurobiology
University Hospital Würzburg, 

Members of the team

Maximilian Koch, PhD Student

Manas Kshirsagar, PhD Student

Ankita Rawat, PhD Student