Therapeutic potential of glycine receptors in pain sensory pathways

感染或受伤引起的炎症会导致痛感增强，并能将非疼痛的刺激(如触摸)转化为痛苦的刺激。这种作用是通过在周围组织和脊髓中产生前列腺素来实现的。前列腺素最近被证明可以降低通常发生在脊髓痛觉神经元上的抑制性神经传递的幅度。这会提高这些神经元的兴奋性，从而使微弱的疼痛刺激更容易传递到大脑。痛感觉神经元的抑制性神经传递在很大程度上是由Alpha3甘氨酸受体亚单位介导的，而这一亚单位在身体其他地方是没有的。人们对这些受体的生理和药理特性知之甚少。我们推测，增加α3甘氨酸受体活性的药物可能为疼痛提供一种新的治疗方法。该项目将首先确定可以增加这些受体激活的新药。然后，它将测试这些药物是否可能在体内起作用。该项目还将确定为什么这些受体只存在于疼痛神经元上。总而言之，这些信息将确定Alpha3甘氨酸受体是否代表着一个有希望的炎症性疼痛的新治疗靶点，并将使我们处于有利地位，开始下一步确定新的治疗先导化合物。

Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, thereby making it easier for weak pain stimuli to be relayed to the brain. Inhibitory neurotransmission onto pain sensing neurons is largely mediated by the alpha3 glycine receptor subunit that is not found anywhere else in the body. Very little is known about the physiological and pharmacological properties of these receptors. We hypothesise that drugs that increase the activation of alpha3 glycine receptors may provide a novel treatment for pain. This project will firstly identify new drugs that can increase the activation of these receptors. It will then test whether these drugs are likely to work in vivo. The project will also establish why these receptors are found only on pain neurons. Together, this information will establish whether alpha3 glycine receptors represent a promising new therapeutic target for inflammatory pain, and will place us in an excellent position to begin the next step of identifying novel therapeutic lead compounds.