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A novel non-synaptic role for glutamate receptors

Blockade of glutamate receptors in peripheral nerve endings inhibits chronic pain


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Professor Dr. Rohini Kuner, Pharmacology Institute, Medical Faculty Heidelberg. Source: private


CellNetworks scientists from the Pharmacology Institute, Medical Faculty Heidelberg have found an important mechanism for chronic pain and have thereby opened new possibilities for a therapeutic approach. It is generally well-accepted that chronic pain comes about via plasticity of neuronal excitability and synaptic transmission in pain pathways, particularly via changes in glutamatergic neurotransmission. So far, it was thought that only synaptic receptors in the central nervous system play a key role in these plasticity processes. However, therapeutic strategies based on blockade of glutamate receptors have failed clinically so far, not due to lack of efficacy but due to serious side effects that come about in the context of cognition and deleterious psychotropic effects on brain function. Peculiarly, however, ultrastructural studies performed several decades ago reported the presence of glutamate receptors at the endings of sensory nerves in the skin of humans and rodents. The functional role of these non-synaptic glutamate receptors was unknown so far. A research team headed by the CellNetworks researcher, Rohini Kuner, in collaboration with the group of Gary Lewin at the Max Delbrück Center for Molecular Medicine (Berlin Buch) have now discovered the function of these non-synaptic glutamate receptors in sensory nerve endings and published these results in the Journal of Clinical Investigation.


The approach used by the Heidelberg team was based upon the use of a genetic strategy to conditionally mutate a subtype of glutamate receptors, namely AMPA receptors, selectively in peripheral nerves without changing their expression in the central nervous system. In contrast to wild-type mice which develop chronic pain hypersensitivity to chemical and mechanical stimuli following inflammation in peripheral organs, these peripheral nociceptor-specific mutants did not develop chronic pain. Using a multi-disciplinary approach involving electrophysiological, behavioural and pharmacological approaches, the team worked out the underlying mechanism which involves calcium influx via AMPA receptors and modulation of nociception-specific ion channels in nerve endings.


Vijayan Gangadharan, the doctoral student who performed this study, explains: “These new results show that non-synaptic glutamate receptors in peripheral nerves function as a gate governing the entry of excitatory drive from the periphery into the central nervous system”. “Our experiments predict that a specific blockade of peripheral glutamate receptors by drugs which do not enter the central nervous system could block chronic inflammatory pain without eliciting central side effects”, says Rohini Kuner. The research group hopes that this might pave the way for the development of new therapeutic strategies.


Original article:

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice. Vijayan Gangadharan, Rui Wang, Bettina Ulzhöfer, Ceng Luo, Rita Bardoni, Kiran Kumar Bali, Nitin Agarwal, Irmgard Tegeder, Ullrich Hildebrandt, Gergely G. Nagy, Andrew J. Todd, Alessia Ghirri, Annette Häussler, Rolf Sprengel, Peter H. Seeburg, Amy B. MacDermott, Gary R. Lewin, Rohini Kuner. The Journal of Clinical Investigation 121(4): 1608-1623, 2011.



Professor Dr. Rohini Kuner

Pharmakologisches Institut

Universität Heidelberg

Im Neuenheimer Feld 366 / 584

69120 Heidelberg

Tel.: 06221-54-8289 / -54-8247

Fax: 06221-54-8549

Email: rohini.kuner@pharma.uni-heidelberg.de



Heidelberg University Hospital and Medical Faculty:

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Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 10,000 employees, training and qualification is an important issue. Every year, around 550,000 patients are treated on an inpatient or outpatient basis in more than 50 clinics and departments with 2,000 beds. Currently, about 3,600 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany.


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