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

据估计，慢性疼痛影响多达20%的人口，可能是一种严重的、使人虚弱的疾病，对个人的生活质量产生深远影响。治疗慢性疼痛的新方法的必要性不仅被现有药物治疗不当的大量人所强调，而且还被与现有药物相关的副作用所强调，最显著的是阿片类药物的成瘾特性(所谓的阿片类药物流行)，目前在美国每年估计有50,000人死亡。检测疼痛是一种正常的生理功能，它保护我们免受伤害和伤害。在这方面，例如，皮肤中的神经细胞持续监测我们的环境，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，在那里这些信号被感知为疼痛，并可以采取适当的行动(例如，避免疼痛的根源)。重要的是，脊髓是疼痛信号通路中的关键通道，具有控制机制，确保外周和大脑之间的“门”只有在需要时才打开。在慢性疼痛中，由于脊髓中的“门”没有正确关闭，信号从外周到大脑的传输不适当。脊髓门是将信息传递到脊髓的神经细胞和将信息传递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缝隙，化学物质甘氨酸从一个神经细胞释放出来，然后通过缝隙扩散，与相邻神经细胞上的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，起着关闭大门的机制。我们的假设是，在慢性疼痛中，门的关闭机制变得薄弱，而不是保持关闭的门，让门打开，以便信号传输到大脑，导致慢性疼痛。我们的药物旨在增强甘氨酸受体的功能(即加强减弱的门关闭机制)，从而关闭门，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.