Neuronal circuits for itch in the spinal dorsal horn

慢性瘙痒是一种令人痛苦的疾病，影响着超过20%的人口。它是许多疾病的特征，包括影响皮肤、肾脏和血液的疾病，以及某些类型的癌症和艾滋病毒感染。这也是某些药物的副作用，如吗啡。对于大多数慢性瘙痒患者来说，没有令人满意的治疗方法，其中四分之一的患者瘙痒超过5年。尽管它在临床上很重要，但我们对导致瘙痒的脊髓和大脑中的神经回路知之甚少。感觉信息进入脊髓，通过涉及不同类型的局部神经细胞(中间神经元)的复杂电路进行处理，然后由一种称为投射神经元的神经细胞传递到大脑。许多不同类型的脊髓中间神经元参与了瘙痒和疼痛的通路。其中一些(兴奋性中间神经元)通过这些回路传递信息，而另一些(抑制性中间神经元)则阻止信息的传递。疼痛的刺激可以有力地抑制瘙痒，这就是为什么抓挠可以暂时缓解的原因。我们已经确定了脊髓中一种减少瘙痒的抑制性中间神经元，并表明这些细胞负责通过抓挠来缓解瘙痒。这些抑制细胞含有一种名为强啡肽的多肽(一种短蛋白)。两种不同类型的兴奋性中间神经元被认为是瘙痒通路的一部分。其中一个含有不同的肽(胃泌素释放肽，GRP)，另一个含有GRP作用的受体(GRP受体，或GRPR)。最近的研究表明，皮肤上的感觉神经纤维激活GRP细胞，然后兴奋GRPR细胞，从而传递瘙痒。来自这些神经元的信息通过瘙痒选择性投射神经元传输到大脑。我们提供的证据表明，抑制性强啡肽细胞通过在GRPR细胞水平上阻断传递来减少瘙痒。在本项目中，我们将测试所建议电路的几个组件。我们已经发现，激活强啡肽细胞可以减少瘙痒，但重要的是要证明，减少它们的活动会增加瘙痒。我们还将测试它们的抑制作用是否对瘙痒具有选择性，或者它是否也能减轻疼痛。众所周知，GRP细胞接受一种类型的瘙痒敏感神经纤维的输入。然而，我们最近发现了一种新的神经纤维，它可能对不同的瘙痒诱导刺激产生反应，我们将看看这些神经纤维是否也针对GRP细胞。GRPR细胞已经与瘙痒有关，因为摧毁它们可以在不影响疼痛的情况下减轻瘙痒。然而，人们对这些细胞知之甚少。我们的初步研究表明，它们对应于一种被称为垂直细胞的兴奋性中间神经元，它为投射神经元提供输入，我们将进行进一步的研究来证实这一点。我们将确定它们接受的感觉输入的类型，以及它们是否对瘙痒(但不是疼痛)刺激做出选择性反应。脊髓这一区域的大多数投射神经元携带疼痛信号，其中一部分是由瘙痒刺激激活的。因此，我们将观察GRPR细胞是否只针对瘙痒激活的投射神经元。我们还将测试强啡肽细胞通过抑制GRPR细胞来抑制瘙痒的预测，并确定它们使用的化学信使。最后，我们将通过增加或减少GRPR细胞的活动，并测试它们对瘙痒和疼痛行为的影响，来确定GRPR细胞是否确实对瘙痒具有关键和选择性。该项目将提供有关脊髓中与瘙痒有关的神经回路的重要新信息。结合关于不同类型神经细胞上存在的药物受体的新信息，它应该有助于开发治疗慢性瘙痒的新方法。

Chronic itch is a distressing condition that affects over 20% of the population. It is a feature of many diseases, including conditions affecting skin, kidneys and blood, as well as some types of cancer and HIV infection. It is also a side-effect of certain drugs, such as morphine. For most patients with chronic itch there are no satisfactory treatments, and a quarter of these patients suffer itch for more than 5 years. Despite its clinical importance, we have only a limited knowledge about the nerve circuits in the spinal cord and brain that are responsible for itch. Sensory information enters the spinal cord and is processed through complex circuits involving different types of local nerve cells (interneurons), before being carried to the brain by a type of nerve cell called a projection neuron. Many different types of spinal cord interneuron are involved in itch and pain pathways. Some of these (excitatory interneurons) transmit information through these circuits, while others (inhibitory interneurons) block the passage of information. Painful stimuli can powerfully suppress itch, which is why scratching provides temporary relief. We have identified a type of inhibitory interneuron in the spinal cord that reduces itch, and shown that these cells are responsible for the relief of itch by scratching. These inhibitory cells contain a peptide (a short protein) called dynorphin. Two different types of excitatory interneuron are thought to be part of the itch pathway. One of these contains a different peptide (gastrin-releasing peptide, or GRP) and the other possesses the receptor on which GRP acts (the GRP receptor, or GRPR).Recent studies have suggested a nerve circuit for transmitting itch, in which sensory fibres from the skin activate GRP cells, which then excite GRPR cells. Information from these is transmitted to the brain via itch-selective projection neurons. We have provided evidence that the inhibitory dynorphin cells reduce itch by blocking transmission at the level of the GRPR cells. In this project, we will test several components of the proposed circuit. We have already found that activating dynorphin cells reduces itch, but it is important to show that reducing their activity increases itch. We will also test whether their inhibitory action is selective for itch, or whether it also reduces pain. The GRP cells are known to receive input from one type of itch-sensitive nerve fibre. However, we recently identified a new class of nerve fibre that is likely to respond to different itch-inducing stimuli, and we will see whether these also target the GRP cells. The GRPR cells are already implicated in itch, because destroying them reduces itching without affecting pain. However, little is known about these cells. Our initial studies suggest that they correspond to a type of excitatory interneuron, known as vertical cells, which provide input to projection neurons, and we will carry out further studies to confirm this. We will determine the types of sensory input they receive, and whether they respond selectively to itchy (but not painful) stimuli. Most projection neurons in this region of the spinal cord carry pain signals, with a subset being activated by itchy stimuli. We will therefore see whether the GRPR cells only target the itch-activated projection neurons. We will also test the prediction that dynorphin cells block itch by inhibiting the GRPR cells, and we will identify the chemical messengers that they use. Finally, we will determine whether the GRPR cells are indeed critical and selective for itch, by increasing or decreasing their activity and testing the effects on itch and pain behaviour.The project will provide important new information about nerve circuits in the spinal cord that are involved in itch. Taken together with emerging information about the drug receptors that are present on different types of nerve cell, it should assist in the development of new treatments for chronic itch.