Spinal inhibitory interneurons that suppress itch

抑制瘙痒的脊髓抑制性中间神经元

• 批准号: MR/L003430/1
• 负责人: Andrew Todd
• 金额: $ 55.92万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL003430%2F1
• 关键词: Spinal; inhibitory; interneurons; suppress; itch

Chronic itch is a distressing feature of many diseases, including conditions affecting the skin, kidneys and blood, as well as certain forms of cancer. It is also a side-effect of certain drugs, such as morphine. Although some types of itch respond to antihistamines, in many cases there are no satisfactory treatments available. At present we have very limited knowledge of the nerve circuits in the spinal cord and brain that transmit itch.Pain can powerfully inhibit itch, which is why scratching produces temporary relief. This inhibition, which occurs in the spinal cord, involves a type of local nerve cell (interneuron) that is activated by painful stimuli and inhibits transmission of the itch signal to cells (known as projection neurons) that convey sensory information to the brain. A recently developed mutant mouse, which lacks a protein called bhlhb5, shows dramatically increased itching, resulting from loss of inhibitory interneurons in the spinal cord. Interestingly, these "bhlhb5 knockout" mice respond normally to most types of painful stimulus, which suggests that the missing interneurons selectively inhibit itch, but not pain. However, because the knockout mouse loses these cells before birth, there may have been compensatory changes, leading to relatively normal pain sensation. One of the main problems with understanding how sensory information is processed in the spinal cord is that there are many different populations of inhibitory interneurons, each with different functions. We have recently found that several populations can be recognised on the basis of the different substances that they contain. In preliminary studies, we have identified two populations that are largely absent from the Bhlhb5 knockout mouse, and it is likely that one or both of these is responsible for the inhibition of itch by painful stimuli.In this project we will test whether one of these populations is responsible for the suppression of itch by pain, and attempt to identify the pathway that underlies this phenomenon. We will initially determine whether the loss of nerve cells is restricted to the two populations we have identified by staining spinal cords from normal and bhlhb5 knockout mice with markers to reveal these cells and all other types of inhibitory interneuron. If these interneurons are responsible for preventing itch, then blocking their activity in normal adult mice should increase itch. We will use two different approaches to test this. First, we will inject a chemical to destroy a relatively large number of inhibitory interneurons, including all of those that are absent in the knockout mice. We will then use a more selective genetic method to destroy or inactivate one of these populations. By examining the responses of these mice to stimuli that normally cause itch or pain, we will improve our understanding of the roles played by these different populations of inhibitory interneurons. We will then investigate the underlying nerve circuits by identifying projection neurons that are activated by itch-inducing stimuli in normal and Bhlhb5 knockout mice. We will test the prediction that one of the populations of inhibitory interneurons that is lost in the knockout mice acts directly on projection neurons that signal itch. Although most pain tests are normal in the knockout mouse, these animals do show an increased response following injection of formalin into the skin. We have identified a type of projection neuron that loses much of its normal inhibitory input in the bhlhb5 knockout mouse, and we will test whether these cells are involved in the abnormal response to formalin.The project will provide valuable insight into the organisation of nerve pathways in the spinal cord that transmit and modify sensory information. This will improve our understanding of pathological itch and pain states, and should help towards the identification of targets for new treatments for these conditions.

慢性瘙痒是许多疾病的一个令人痛苦的特征，包括影响皮肤、肾脏和血液的病症，以及某些形式的癌症。它也是某些药物的副作用，如吗啡。虽然某些类型的瘙痒对抗组胺药有反应，但在许多情况下没有令人满意的治疗方法。目前，我们对脊髓和大脑中传递瘙痒的神经回路的了解非常有限。疼痛可以有效地抑制瘙痒，这就是为什么抓挠可以产生暂时的缓解。这种抑制发生在脊髓中，涉及一种局部神经细胞（中间神经元），它被疼痛刺激激活，并抑制瘙痒信号向细胞（称为投射神经元）的传递，这些细胞将感觉信息传递给大脑。最近开发的一种突变小鼠，缺乏一种叫做bhlhb5的蛋白质，表现出明显增加的瘙痒，这是由于脊髓中抑制性中间神经元的丢失。有趣的是，这些“bhlhb5基因敲除”的小鼠对大多数类型的疼痛刺激反应正常，这表明缺失的中间神经元选择性地抑制瘙痒，而不是疼痛。然而，由于基因敲除小鼠在出生前就失去了这些细胞，可能已经出现了代偿性变化，导致相对正常的痛觉。理解感觉信息如何在脊髓中处理的主要问题之一是，有许多不同的抑制性中间神经元群体，每一个都有不同的功能。我们最近发现，几个种群可以根据它们所含的不同物质来识别。在初步的研究中，我们已经确定了两个群体，这是在很大程度上缺乏的Bhlhb5基因敲除小鼠，它很可能是其中之一或两者都是负责抑制瘙痒的疼痛刺激。在这个项目中，我们将测试是否这些群体之一是负责抑制瘙痒的疼痛，并试图确定这种现象背后的途径。我们将首先确定神经细胞的丢失是否仅限于我们通过用标记物对正常和bhlhb5敲除小鼠的脊髓进行染色来识别的两个群体，以揭示这些细胞和所有其他类型的抑制性中间神经元。如果这些中间神经元负责防止瘙痒，那么在正常成年小鼠中阻断它们的活性应该会增加瘙痒。我们将使用两种不同的方法来测试这一点。首先，我们将注射一种化学物质来破坏相对大量的抑制性中间神经元，包括敲除小鼠中不存在的所有抑制性中间神经元。然后，我们将使用一种更具选择性的遗传方法来摧毁或消灭其中一个种群。通过检查这些小鼠对通常引起瘙痒或疼痛的刺激的反应，我们将提高对这些不同抑制性中间神经元群体所起作用的理解。然后，我们将通过识别正常和Bhlhb5基因敲除小鼠中由瘙痒诱导刺激激活的投射神经元来研究潜在的神经回路。我们将测试这样的预测，即在敲除小鼠中丢失的抑制性中间神经元群体之一直接作用于发出瘙痒信号的投射神经元。尽管基因敲除小鼠的大多数疼痛测试都是正常的，但这些动物在皮肤注射福尔马林后确实表现出增加的反应。我们已经在bhlhb5基因敲除小鼠中发现了一种投射神经元，这种神经元失去了大部分正常的抑制性输入，我们将测试这些细胞是否参与了对福尔马林的异常反应，该项目将为研究脊髓中传递和修改感觉信息的神经通路的组织提供有价值的见解。这将提高我们对病理性瘙痒和疼痛状态的理解，并有助于确定这些疾病的新治疗目标。

项目成果

Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.

• DOI: 10.1016/j.neuron.2014.02.046
• 发表时间: 2014-05-07
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kardon AP;Polgár E;Hachisuka J;Snyder LM;Cameron D;Savage S;Cai X;Karnup S;Fan CR;Hemenway GM;Bernard CS;Schwartz ES;Nagase H;Schwarzer C;Watanabe M;Furuta T;Kaneko T;Koerber HR;Todd AJ;Ross SE
• 通讯作者: Ross SE

Circuit dissection of the role of somatostatin in itch and pain.

生长抑素在瘙痒和疼痛中作用的电路剖析

• DOI: 10.1038/s41593-018-0119-z
• 发表时间: 2018-05
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Huang J;Polgár E;Solinski HJ;Mishra SK;Tseng PY;Iwagaki N;Boyle KA;Dickie AC;Kriegbaum MC;Wildner H;Zeilhofer HU;Watanabe M;Riddell JS;Todd AJ;Hoon MA
• 通讯作者: Hoon MA

The organisation of spinoparabrachial neurons in the mouse.

• DOI: 10.1097/j.pain.0000000000000270
• 发表时间: 2015-10
• 期刊: Pain
• 影响因子: 7.4
• 作者: Cameron D;Polgár E;Gutierrez-Mecinas M;Gomez-Lima M;Watanabe M;Todd AJ
• 通讯作者: Todd AJ

Immunostaining for Homer reveals the majority of excitatory synapses in laminae I-III of the mouse spinal dorsal horn.

• DOI: 10.1016/j.neuroscience.2016.05.009
• 发表时间: 2016-08-04
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Gutierrez-Mecinas M;Kuehn ED;Abraira VE;Polgár E;Watanabe M;Todd AJ
• 通讯作者: Todd AJ

Preprotachykinin A is expressed by a distinct population of excitatory neurons in the mouse superficial spinal dorsal horn including cells that respond to noxious and pruritic stimuli.

• DOI: 10.1097/j.pain.0000000000000778
• 发表时间: 2017-03
• 期刊: Pain
• 影响因子: 7.4
• 作者: Gutierrez-Mecinas M;Bell AM;Marin A;Taylor R;Boyle KA;Furuta T;Watanabe M;Polgár E;Todd AJ
• 通讯作者: Todd AJ