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

鉴定小鼠神经病理性损伤后引起厌恶行为的特定低阈值初级传入神经

• 批准号: 10178131
• 负责人: Joseph J Salsovic
• 金额: $ 3.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178131
• 关键词: Affect; Alleles; Amyloid beta-Protein; Animals; Automobile Driving; Back; Behavior; Behavioral Model; Brain; Brain Stem; Clinical; Cutaneous; Disease; Electric Capacitance; Electrophysiology (science); Hypersensitivity; Injury; Knowledge; Label; Lead; Lesion; Light; Mechanical Stimulation; Mechanics; Mediating; Membrane; Membrane Potentials; Mus; Nerve; Nervous system structure; Neurons; Neuropathy; Nociception; Pain; Patients; Peripheral Nervous System Diseases; Population; Preparation; Property; Resistance; Response to stimulus physiology; Rest; Rhodopsin; Rodent; Sensory; Sensory Thresholds; Skin; Source; Spinal; Spinal Cord; Stimulus; Thalamic structure; Therapeutic; Time; Transgenic Mice; Whole-Cell Recordings; allodynia; awake; common symptom; experimental study; mechanical allodynia; optogenetics; painful neuropathy; response; somatosensory

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.

项目概要/摘要 全球多达 10% 的人口受到因神经损伤或疾病引起的神经性疼痛的影响 体感神经系统。神经性疼痛的常见症状是动态机械性异常性疼痛， 轻刷皮肤会感到极度疼痛的情况。很多患者都患有 机械性异常性疼痛对当前的治疗没有反应。在神经病患者中，众所周知 机械性异常性疼痛需要激活有髓鞘低阈值初级传入神经。然而，有 这些传入神经和参与驱动异常性疼痛的特定主要传入亚型具有显着的多样性 未知。研究还表明，椎板 1 脊髓投射神经元接收来自初级的输入。 传入和投射到大脑，在神经性损伤后对机械刺激变得敏感，并且 据认为参与介导异常性疼痛。因此，我假设特定的低- 阈值机械感受初级传入亚型为第 1 椎板提供更大的输入 投射神经元并在神经性损伤后引起小鼠厌恶。在目标 1 中，天真且神经病 小鼠，我建议使用脊髓-神经-皮肤离体制剂来激活低阈值的特定亚型 使用光遗传学进行初级传入，同时从背面标记的第 1 层脊髓投射神经元进行记录。在 在这些初步研究中，我将检查三种对光反应良好的不同低阈值传入亚型 刷皮肤，包括 Aδ 低阈值传入神经、Aβ 具有披针形末端的快速适应传入神经， 和具有圆周末端的 Aβ 传入神经。作为异常性疼痛的潜在电生理学基础，结果 将确定低阈值初级传入神经的哪些亚型为第 1 层脊柱投射提供更大的输入 神经病理性损伤后的神经元。在目标 2 中，在行为模型中，我将采用 LED 照明场所厌恶 在幼稚小鼠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。这里， 结果将确定哪些低阈值初级传入神经病后导致厌恶行为 受伤。总之，事实证明，阻断所有低阈值初级传入神经可以减轻机械性 患者出现异常性疼痛，但参与异常性疼痛的具体传入神经亚型尚不清楚。这些知识 可能会产生从根源上阻断异常性疼痛同时保持大部分皮肤感觉的治疗方法 传入。