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

用于治疗慢性疼痛的脊髓甘氨酸受体变构调节剂。

• 批准号: MR/W029375/1
• 负责人: John Atack
• 金额: $ 276.26万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW029375%2F1
• 关键词: Allosteric; modulators; spinal; cord; glycine

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.

据估计，慢性疼痛影响了多达20%的人口，这是一种严重的、使人衰弱的疾病，对个人的生活质量有深远的影响。我们迫切需要一种治疗慢性疼痛的新方法，这不仅是因为现有药物治疗效果差的人数众多，而且还因为现有药物的副作用，最明显的是阿片类药物的成瘾性（所谓的“阿片类流行病”），目前美国每年约有5万人死于阿片类药物。检测疼痛是一种正常的生理功能，可以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，在那里信号被感知为疼痛并采取适当的行动（例如，避免疼痛的来源）。重要的是，脊髓作为疼痛信号通路的关键通道，通过控制机制确保外周神经和大脑之间的“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，从外周到大脑的信号传递不适当。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间隙，化学甘氨酸从一个神经细胞释放出来然后扩散穿过间隙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，起着门关闭机制的作用。我们的假设是，在慢性疼痛中，不是保持一个关闭的门，而是门关闭机制被削弱，让信号传递到大脑的门打开，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（即加强减弱的门关闭机制），从而关闭门，防止异常疼痛信号传导，这是慢性疼痛的基础。