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

项目摘要/摘要 多达10%的全球人口受到由病变或疾病引起的神经病理性疼痛的影响 躯体感觉神经系统。神经病理性疼痛的一个常见症状是动力性机械异位痛，即 轻刷皮肤被认为是极度疼痛的状态。许多患者患有 机械性异位痛症对目前的治疗没有反应。在神经病患者中，众所周知， 机械性痛觉异常需要激活有髓鞘的低阈值初级传入。然而，在那里 在这些传入和参与驱动痛觉异常的特定初级传入亚型中具有显著的多样性 都是未知的。也有研究表明，1层脊髓投射神经元接受来自初级 传入和投射到大脑，在神经性损伤后对机械刺激敏感，并 被认为参与调节痛觉过敏症。因此，我假设激活特定的低电平- 机械感受性初级传入亚型为1椎板提供更大的输入 在小鼠神经病理性损伤后投射神经元并引起厌恶。在目标1中，天真和神经病态 小鼠，我建议使用一种脊髓-神经-皮肤体外制剂来激活特定亚型的低阈值 利用光遗传学进行初级传入，同时记录背侧标记的1层脊髓投射神经元。在……里面 在这些初步的研究中，我将检查三种不同的低阈值传入亚型，它们对光的反应良好 刷皮，包括Aδ低阈值传入，Aβ快速适应披针形末梢的传入， Aβ以环状末梢为传入单位。作为治疗痛觉异常的潜在电生理学基础，研究结果 将确定哪些亚型的低阈值初级传入对1层脊髓投射有更大的输入 神经病理性损伤后的神经元。在目标2中，在一个行为模型中，我将使用LED照明的位置厌恶 在幼稚和神经病小鼠中使用光遗传学激活特定的低阈值传入的实验。这里, 结果将确定哪些低阈值的初级传入会导致神经病后的厌恶行为 受伤。综上所述，阻断所有低阈值的初级传入可以减轻机械性传入 患者中存在痛觉异常，但参与痛觉异常的传入神经的具体亚型尚不清楚。这一知识 可能会导致治疗方法，从源头上阻止痛觉异常，同时保持大部分皮肤感觉 传入器。

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.