GABA Inhibition of Glutamate

Wind-up Pain is the Hallmark of the Disease of Chronic Pain. It is precipitated by activation of normally dormant NMDA receptors blocked by Magnesium in the natural state.

NMDA receptors are located throughout he CNS and serve the normal function of killing damaged neurons so that they can be replaced with new neurons. In Chronic Pain states NMDA receptors are activated by the pairing of non-NMDA Glutamatergic receptors (AMPA and Kinate receptors) and Substance-P activated Neurokinin-1 receptors. Activated NMDA receptors cause influx of Calcium into Dorsal Horn Wide Dynamic Range interneurons resulting in a cycle of increased production of NMDA receptors, increased sensitization of NMDA receptors, increased release of Glutamate at presynaptic sites and increased release of Substance-P at presynaptic sites. This positive feedback loop results in a marked increase in the pain signal ultimately perceived by the brain.

GABA neurons in the Dorsal Horn synapse with incoming presynaptic Glutamate end terminals. When GABA transmitters activate GABA receptors on the Glutamatergic nerve terminals, Chloride channels are opened and release of Glutamate and Substance-P is inhibited. It is thought that GABA-B plays a larger role than GABA-A in this process, but this is not entirely clear.

Tiagabine is unique in its action as a Selective GABA Reuptake Inhibitor (SGRI). It blocks GABA Transport-1 (GAT-1) active transport of GABA from the synapse back into the presynaptic cell. The result is that of longer availability of GABA in the synapse with more robust coverage of GABA post synaptic receptor sites.

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