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

据估计，慢性疼痛影响高达20%的人口，可能是一种严重的和使人衰弱的疾病，对个人的生活质量有深远的影响。需要一种新的治疗慢性疼痛的方法，这不仅是因为大量的人没有得到现有药物的良好治疗，而且还因为与现有药物相关的副作用，最明显的是阿片类药物的成瘾性（所谓的"阿片类药物流行病"），目前在美国估计每年有50，000人死亡。保护我们免受伤害的生理功能。在这方面，例如，皮肤中的神经细胞持续监测我们的环境，并且当它们检测到潜在的有害情况时，信号通过脊髓发送到大脑，在那里信号被感知为疼痛和适当的动作（例如，避免疼痛的来源）。重要的是，脊髓是疼痛信号通路中的关键通道，其控制机制确保外周和大脑之间的"门"只在需要时打开。在慢性疼痛中，由于脊髓中的"门"没有正确关闭，因此从外周到大脑的信号传输不适当。脊髓门是将信息带入脊髓的神经细胞和将信息带到大脑的神经细胞之间的连接（突触）。神经细胞之间的连接实际上是一个物理间隙，化学甘氨酸从一个神经细胞中释放出来，然后扩散穿过差距，与相邻神经细胞上的一种特定蛋白质，甘氨酸受体相互作用，正是这种蛋白质，甘氨酸受体，起着门关闭机制的作用。我们的假设是，在慢性疼痛中，门关闭机制变得减弱，而不是保持关闭的门，使门打开，以便将信号传递到大脑，从而导致慢性疼痛。我们的药物旨在增强甘氨酸受体的功能（即，加强弱化的闸门关闭机制），从而关闭闸门并防止作为慢性疼痛基础的异常疼痛信号。

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.