Dextromethorphan is a drug most commonly used as a cough suppressant present in many over the counter cough medication. Coughing is activated in the cough center of the brain, which is located in the medulla oblongata, What receptors are targeted by Dextromethorphan is known, but the exact mechanism is unknown. Its metabolite dextrorphan acts in a very similar way. Dextromethorphan inhibits NMDA receptors, nicotinic acetylcholine receptors, and sigma-1 receptors. Dextromethorphan is an agonist of NMDA and sigma-1 receptors. It is an antagonist of neuronal acetylcholine receptors, especially the α3/β4 nicotinic receptors. Glutamate is synthesized from glutamine in either the neuron or glial cells nearby. It is stored as glutamine in the glial cells until it is required. Once released it normally activates glutamate NMDA receptors, however, Dextromethorphan binds to NMDA receptors subunit 3A and prevents glutamate from binding to the NDMA receptor on the epsilon-2 subunit. This prevents the calcium channel from opening and allowing calcium into to the post-synaptic neuron. With calcium unable to enter the neuron, the neuron cannot depolarize which stops the signal or makes it much more difficult to get a signal through the neurons.This receptor is likely located in the cough center of the brain which is mostly unknown beyond being somewhere in the medulla oblongata. Sigma-1 receptors have a high affinity for binding to synthetic compounds such as Dextromethorphan. Sigma-1 receptors do not seem to have any role in preventing coughing. They are present in the endoplasmic reticulum of central nervous system neurons, where they regulate calcium and potassium, but the reason for that is not well understood. The side-effects Dextromethorphan causes because of its affinity for Sigma-1 receptors are not much better understand than the effects it has on coughing.

Dextromethorphan NMDA Antagonism Pathway References