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A novel non-synaptic role for glutamate receptors
Posted May 20 2011
...blockade of glutamate receptors in peripheral nerve endings inhibits chronic pain

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, ultra-structural 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 electro-physiological, 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. Gangadharan V, Wang R, Ulzhöfer B, Luo C, Bardoni R, Bali KK, Agarwal N, Tegeder I, Hildebrandt U, Nagy GG, Todd AJ, Ghirri A, Häussler A, Sprengel R, Seeburg PH, Macdermott AB, Lewin GR, Kuner R. J Clin Invest. 2011 Apr 1;121(4):1608-23. doi: 10.1172/JCI44911.

 

 

Contact:
Professor Dr. Rohini Kuner
Institute for Pharmacology
Universität Heidelberg
Im Neuenheimer Feld 366/ 584
69120 Heidelberg
Phone: 06221-54-8289/-54-8247
Fax: 06221-54-8549
Email: rohini.kuner [ aT ] pharma.uni-heidelberg.de