Allosteric modulators of spinal cord glycine receptors for the treatment of chronic pain.

Chronic pain, which has been estimated to affect up to 20% of the population, can be a severe and debilitating disorder with a profound impact upon an individual's quality of life. The need for a new way of treating chronic pain is emphasized not only by the large number of people that are poorly treated by existing medications, but also the side-effects associated with existing drugs, most notably the addictive properties of opioid drugs (the so-called "opioid epidemic") that currently accounts for an estimated 50,000 deaths per year in the U.S. The detection of pain is a normal, physiological function that protects us from injury and harm. In this regard, nerve cells in the skin, for example, continually monitor our environment and when they detect a potential harmful situation, signals are sent via the spinal cord to the brain where the signals are perceived as pain and appropriate action (e.g., avoiding the source of the pain) can be taken. Importantly, the spinal cord acts as a key gateway in the pain signalling pathway with control mechanisms ensuring that the "gate" between the periphery and the brain is only open when needed. In chronic pain, there is an inappropriate transmission of signals from the periphery to the brain due to the "gate" in the spinal cord not being properly closed. The spinal cord gate is the connection (synapse) between the nerve cell bringing information into the spinal cord and the nerve cell that then carries that information to the brain. The connection between nerve cells is actually a physical gap and the chemical glycine is released from one nerve cell which then diffuses across the gap to interact with a specific protein, the glycine receptor, on the adjacent nerve cell and it is this protein, the glycine receptor, that acts as a gate closure mechanism. Our hypothesis is that rather than maintaining a closed gate, in chronic pain the gate closure mechanism becomes weakened, leaving the gate open for signals to be transmitted to the brain resulting in chronic pain. Our drug aims to enhance the function of glycine receptors (i.e., strengthen the weakened gate closure mechanism), thereby closing the gate and preventing the abnormal pain signalling that is the basis of chronic pain.