Role of A- and M-type K+ and Ih currents and channels in spontaneous pain

A 型和 M 型 K 和 Ih 电流和通道在自发性疼痛中的作用

• 批准号: G0700420/1
• 负责人: Laiche Djouhri
• 金额: $ 47.67万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700420%2F1
• 关键词: Role; type; K+; Ih; currents

Chronic pain affects approximately one-sixth of the population at some time in their lives. Pain usually results from tissue damage, but in some diseases spontaneous pain can occur: this pain is independent of any tissue injury. Spontaneous pain can be devastating and remains very hard to treat because its underlying mechanisms are not understood. Recently, we discovered that the degree of spontaneous pain is related to the rate of spontaneous firing of action potentials (nerve impulses) in a subpopulation of pain-sensing neurons. We aim to clarify the underlying mechanisms of these spontaneous impulses.Nerve impulses normally carry information from sensory receptors in the skin towards the central nervous system. These impulses signal touch, temperature or pain; normally pain signals result only from actual or threatened tissue damage, but spontaneous impulses in pain-signalling nerve fibres will produce a sensation of pain. Nerve impulses are generated by protein molecules (ion channels) that regulate the flow of ions (mainly sodium and potassium) across the membrane. Potassium ions move outwards, making the nerve more negative inside and reducing the likelihood of impulses being generated. In contrast, sodium ions move inwards, making the nerve more positive inside and increasing the tendency to fire impulses.This proposal focuses on ion channels that are open under resting conditions and allow potassium ions to leave the nerve fibre (through subtypes known as A-type and M-type potassium channels) or sodium ions to enter (through a channel subtype known as HCN). The hypothesis is that reducing expression or activity of A- or M-type channels, and/or increasing expression or activity of HCN channels, would increase the tendency of a pain-signalling nerve fibre to generate spontaneous impulses and thus create the sensation of pain.We shall test this hypothesis by recording electrical currents and voltage changes caused by these channels in sensory neurons in rat in vivo. We aim to determine in animal models of chronic pain whether spontaneous firing and spontaneous pain behaviour are affected by blocking or opening these channels with pharmacological agents. We shall also dye-inject spontaneously active neurons enabling us to use labeled antibodies to detect which proteins (including ion channels) are being expressed in these neurons, and to determine whether expression of these ion channels is altered by agents causing inflammation which are known to increase spontaneous impulse generation.

慢性疼痛影响大约六分之一的人口在他们生命中的某个时候。疼痛通常由组织损伤引起，但在某些疾病中可能发生自发性疼痛：这种疼痛与任何组织损伤无关。自发性疼痛可能是毁灭性的，仍然很难治疗，因为它的潜在机制还不清楚。最近，我们发现自发性疼痛的程度与疼痛感觉神经元亚群中动作电位（神经冲动）的自发放电速率有关。我们的目的是阐明这些自发性冲动的潜在机制。神经冲动通常将信息从皮肤的感觉受体传递到中枢神经系统。这些脉冲信号触摸，温度或疼痛;通常疼痛信号只产生于实际或威胁性的组织损伤，但疼痛信号神经纤维中的自发脉冲会产生疼痛感。神经冲动是由蛋白质分子（离子通道）产生的，它调节离子（主要是钠和钾）穿过膜的流动。钾离子向外移动，使神经内部更负，减少产生冲动的可能性。相反，钠离子向内移动，使神经内部更积极，并增加冲动的倾向。该提议关注在静息条件下开放的离子通道，并允许钾离子离开神经纤维（通过称为A型和M型钾通道的亚型）或钠离子进入（通过称为HCN的通道亚型）。我们的假设是，减少A型或M型通道的表达或活性，和/或增加HCN通道的表达或活性，将增加疼痛信号神经纤维产生自发冲动的倾向，从而产生痛觉，我们将通过记录这些通道引起的电流和电压变化来验证这一假设在大鼠体内感觉神经元。我们的目的是确定在慢性疼痛的动物模型是否自发放电和自发疼痛行为的影响，通过阻断或开放这些通道与药理学药物。我们还将染料注射自发活动的神经元，使我们能够使用标记的抗体来检测哪些蛋白质（包括离子通道）在这些神经元中表达，并确定这些离子通道的表达是否被引起炎症的药物改变，这些药物已知会增加自发冲动的产生。