Examining the roles A-delta LTMRs and BDNF signaling play in neuropathic pain after SCI

检查 A-delta LTMR 和 BDNF 信号在 SCI 后神经病理性疼痛中的作用

• 批准号: 9973251
• 负责人: Sandra M. Garraway
• 金额: $ 38.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973251
• 关键词: Adult; Affect; Air; Anatomy; Arousal; Axon; Behavioral; Brain-Derived Neurotrophic Factor; Caliber; Cellular Assay; Chest; Chronic; Contusions; Cutaneous; Detection; Development; Electrophysiology (science); Environmental Wind; Epithelial; Epithelium; Fiber; Hair Cells; Heart; Heterogeneity; Histologic; In Vitro; Injury; Investigation; Isolectin; Knowledge; Lead; Lesion; Ligands; Measurable; Measures; Mechanics; Mechanoreceptors; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Movement; Mus; NGFR Protein; Nerve; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 2; Nociceptors; Optics; Outcome; Pain; Peripheral; Pharmacology Study; Phenotype; Play; Preparation; Process; Property; Resolution; Role; Sensory; Signal Transduction; Skin; Slice; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord injury; Substance P Receptor; Synapses; Tactile; Techniques; Testing; Touch sensation; Transgenic Mice; Ultrasonics; allodynia; axonal sprouting; behavior test; capsaicin receptor; central sensitization; chronic neuropathic pain; clinically relevant; dermatome; dorsal horn; dorsolateral tract structure; electric field; experimental study; indexing; innovation; mRNA Expression; mechanical allodynia; mouse model; neurochemistry; neuromechanism; neurophysiology; novel; optogenetics; painful neuropathy; preference; protein expression; receptive field; recruit; relating to nervous system; respiratory; response; sensor; spinal nerve posterior root; tool; vocalization

Project Summary/Abstract We propose that afferent plasticity at their peripheral and central terminals plays a critical role in chronic neuropathic pain, expressed as allodynia, after SCI. A-LTMRs, a group of small diameter myelinated afferents that innervate the hairy skin, have recently been shown to signal directionality of touch. They can be identified by their expression of the BDNF receptor, TrkB. A-LTMRs require BDNF-TrkB signaling for normal mechanosensory functions. BDNF and TrkB are implicated in many adaptive and maladaptive processes, including pain. However, it is not clear what role they play in neuropathic pain after SCI. We hypothesize that maintained maladaptive peripheral plasticity involving BDNF-TrkB signaling produces hyperexcitability of A-LTMRs, in turn lead to at-level pain after SCI. In fact, we propose that SCI transforms A-LTMRs into allodynia-encoding nociceptors in dermatomes adjacent to the injury and that this transformation is in part due to the immense spatial and temporal plasticity SCI imposes on BDNF-TrkB signaling. The proposed study consisting of 3 specific aims will be done in transgenic mice which will enable us to selectively target TrkB-expressing A-LTMRs, in intact subjects and after T10 moderate to severe contusion SCI. In SA 1, electrophysiological studies using the ex-vivo skin-nerve, in-vitro adult mouse model and spinal slices with attached dorsal roots in TrkB::ChR2 mice will assess SCI effects on A-LTMRs recruitment, firing and synaptic responses. We will also examine SCI-induced expansion A-LTMRs’ receptive field, as a potential outcome of peripheral afferent sprouting (SA 2). SA 2 will examine anatomical and neurochemical plasticity of A-LTMRs, and changes in BDNF and TrkB expression in the spinal cord, skin and DRG. SA 3 will employ behavioral tests to investigate A-LTMRs’ role in the development of at-level mechanical allodynia after SCI using modified place escape/aversion paradigms, and measures of audible and ultrasonic vocalizations following mechanical and optical stimulation. We will also incorporate novel ultrasensitive movement detection sensors for continuous monitoring of respiratory rates, which is a measurable index of sympathetic arousal that may also be indicative of pain. This innovative and clinically-relevant study will be the first to identify A-LTMR plasticity as a neural mechanism of at-level mechanical allodynia after SCI and that peripheral plasticity mediates the transformation of cutaneous touch afferent into nociceptors. The results obtained from this study will increase our knowledge of the neurophysiological mechanisms that underlie maladaptive sensory processing and pain after SCI.

项目概要/摘要 我们认为，外周和中央末端的传入可塑性在慢性疾病中起着至关重要的作用。 SCI 后的神经性疼痛，表现为异常性疼痛，A-LTMR，一组小直径有髓鞘传入神经。 神经支配毛茸茸的皮肤，最近被证明可以发出触摸的方向性信号，它们可以被识别。 通过表达 BDNF 受体，TrkB 需要 BDNF-TrkB 信号传导才能正常。 BDNF 和 TrkB 与许多适应性和适应不良过程有关。 然而，尚不清楚它们在 SCI 后的神经性疼痛中起什么作用。 我们保留了涉及 BDNF-TrkB 信号传导的维持不良外周可塑性 A-LTMR 的过度兴奋反过来会导致 SCI 后的水平疼痛。事实上，我们认为 SCI 会发生转变。 A-LTMR 进入损伤附近皮区中编码异常性疼痛的伤害感受器，并且这 转变部分归因于 SCI 对 BDNF-TrkB 施加的巨大空间和时间可塑性 拟议的研究包括 3 个具体目标，将在转基因小鼠中完成，这将使我们能够 在完整受试者中以及 T10 中度至重度挫伤后选择性靶向表达 TrkB 的 A-LTMR SCI。 在 SA 1 中，使用离体皮肤神经、体外成年小鼠模型和脊髓切片进行电生理学研究 TrkB::ChR2 小鼠中带有附着的背根将评估 SCI 对 A-LTMR 募集、激发和 我们还将检查 SCI 诱导的 A-LTMR 感受野扩张，作为潜在的。 外周传入萌芽（SA 2）的结果 SA 2 将检查解剖学和神经化学可塑性。 A-LTMR，以及脊髓、皮肤和 DRG 中 BDNF 和 TrkB 表达的变化将采用 SA 3。 行为测试研究 A-LTMR 在 SCI 后水平机械异常性疼痛发生中的作用 使用修改后的地方逃避/厌恶范式，以及可听和超声波发声的测量 在机械和光学刺激之后，我们还将采用新颖的超灵敏运动检测。 用于连续监测呼吸频率的传感器，这是交感神经兴奋的可测量指数 也可能是疼痛的一个指标。 这项创新且与临床相关的研究将首次将 A-LTMR 可塑性确定为神经元 SCI 后水平机械异常性疼痛的机制以及外周可塑性介导的转化 这项研究获得的结果将增加我们的知识。 SCI 后感觉适应不良处理和疼痛的神经生理学机制。