Identification of the specific low-threshold primary afferents that elicit aversive behavior after neuropathic injury in mice

项目总结/摘要 高达10%的全球人口受到神经性疼痛的影响，所述神经性疼痛是由神经系统的病变或疾病引起的。 躯体感觉神经系统神经性疼痛的常见症状是动态机械性异常性疼痛， 轻轻刷一下皮肤就会感觉到极度疼痛的状态。许多患者患有 机械性异常性疼痛对目前的治疗没有反应。在神经病患者中， 机械性异常性疼痛需要激活有髓鞘的低阈值初级传入神经。但 这些传入神经和参与驱动异常性疼痛的特定初级传入神经亚型存在显著的多样性 是未知的。研究还表明，接受初级传入的脊髓投射神经元， 传入神经并投射到大脑，在神经性损伤后对机械刺激变得敏感， 被认为参与介导异常性疼痛。因此，我假设特定的低- 阈值机械感受性初级传入亚型提供更大的输入到椎板1脊髓 投射神经元，并在神经病理性损伤后引起小鼠的厌恶。在目标1中，在初治和神经病患者中 小鼠，我建议使用脊髓神经皮肤离体制剂激活特定亚型的低阈值 使用光遗传学的初级传入，同时从背标记的椎板1脊髓投射神经元记录。在 在这些初步研究中，我将检查三种不同的低阈值传入亚型，它们对光反应良好 刷洗皮肤，包括Aδ低阈值传入，Aβ快速适应性传入，具有披针形末梢， Aβ传入纤维有环形末梢。作为异常性疼痛的潜在电生理基础， 将确定哪些低阈值初级传入神经亚型为第1层脊髓投射提供更多输入 神经损伤后的神经元。在目标2中，在一个行为模型中，我将使用一个LED照明的地方厌恶 在幼稚和神经病小鼠中使用光遗传学激活特定低阈值传入的实验。在这里， 结果将确定哪些低阈值初级传入有助于神经性疾病后的厌恶行为。 损伤总之，已经表明，阻断所有低阈值初级传入神经会导致机械性 异常性疼痛，但涉及异常性疼痛的传入神经的具体亚型尚不清楚。这些知识 可以导致在其源头阻断异常性疼痛同时维持大部分皮肤感觉的治疗 传入神经

Project Summary/Abstract Up to 10% of the global population is affected by neuropathic pain caused by lesions or disease to the somatosensory nervous system. A common symptom of neuropathic pain is dynamic mechanical allodynia, a condition in which light brushing of the skin is perceived as extremely painful. Many patients that suffer from mechanical allodynia do not respond to current treatments. In neuropathic patients, it is well-established that the activation of myelinated low-threshold primary afferents is required for mechanical allodynia. However, there is significant diversity in these afferents and the specific primary afferent subtypes involved in driving allodynia are unknown. It has also been shown that lamina 1 spinal projection neurons, which receive input from primary afferents and project to the brain, become sensitized to mechanical stimuli after neuropathic injury and are thought to be involved in mediating allodynia. Therefore, I hypothesize that the activation of specific low- threshold mechanoreceptive primary afferent subtypes provide greater input to lamina 1 spinal projection neurons and cause aversion in mice after neuropathic injury. In Aim 1, in naïve and neuropathic mice, I propose to use a spinal cord-nerve-skin ex-vivo preparation to activate specific subtypes of low-threshold primary afferent using optogenetics while recording from back-labeled lamina 1 spinal projection neurons. In these initial studies, I will examine three different low-threshold afferent subtypes that respond well to light brushing of the skin, including Aδ low-threshold afferents, Aβ rapidly adapting afferents with lanceolate endings, and Aβ afferents with circumferential endings. As a potential electrophysiological basis for allodynia, the results will determine which subtypes of low-threshold primary afferents give greater input to lamina 1 spinal projection neurons after neuropathic injury. In Aim 2, in a behavioral model, I will employ an LED-lit place aversion experiment to activate specific low-threshold afferents using optogenetics in naïve and neuropathic mice. Here, the results will determine which low-threshold primary afferents contribute to aversive behavior after neuropathic injury. In conclusion, it has been shown that blocking all low-threshold primary afferents alleviates mechanical allodynia in patients, but the specific subtypes of afferents involved in allodynia are not known. This knowledge may lead to therapeutics that block allodynia at its source while maintaining the majority of cutaneous sensory afferents.