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

大约六分之一的人在一生中的某个时候会受到慢性疼痛的影响。疼痛通常是由组织损伤引起的，但在某些疾病中可能会发生自发性疼痛：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，而且仍然很难治疗，因为其潜在的机制尚不清楚。最近，我们发现自发性疼痛的程度与痛感觉神经元亚群中动作电位(神经冲动)的自发放电率有关。我们的目标是阐明这些自发冲动的潜在机制。神经冲动通常将信息从皮肤中的感觉受体传递到中枢神经系统。这些脉冲发出触摸、温度或疼痛的信号；正常情况下，疼痛信号只由实际或先兆的组织损伤产生，但发出疼痛信号的神经纤维中的自发脉冲会产生痛感。神经冲动是由蛋白质分子(离子通道)产生的，这些分子调节离子(主要是钠和钾)通过膜的流动。钾离子向外移动，使神经内部的负性更强，降低了产生冲动的可能性。相反，钠离子向内移动，使神经内部更积极，增加了激发脉冲的倾向。这项建议侧重于在休息条件下开放的离子通道，允许钾离子离开神经纤维(通过A型和M型钾通道)或钠离子进入(通过通道亚型HCN)。假设减少A或M型通道的表达或活性，和/或增加HCN通道的表达或活性，将增加痛信号神经纤维产生自发冲动的倾向，从而产生痛感。我们将通过记录这些通道在活体大鼠感觉神经元中引起的电流和电压变化来检验这一假说。我们的目标是确定在慢性疼痛的动物模型中，自发放电和自发疼痛行为是否受到药物阻断或开放这些通道的影响。我们还将给自发活跃的神经元注射染料，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介质改变，这些介质已知会增加自发冲动的产生。

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.