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.

项目摘要/摘要 我们建议在其外围和中央终端的传入可塑性在慢性中起着至关重要的作用 SCI之后，神经性疼痛表示为异常性痛。 A-LTMR，一组小直径的髓鞘传入 这种支配毛皮的皮肤最近已被证明表明了触摸的方向性。他们可以被识别 通过其表达BDNF受体TrkB。 A-LTMR需要bdnf-trkb信号传导正常 机理感觉函数。 BDNF和TRKB在许多自适应和不良适应过程中实施， 包括疼痛。但是，尚不清楚他们在SCI之后在神经性疼痛中扮演什么角色。 我们假设涉及BDNF-TRKB信号传导保持不良适应性的外围可塑性 A-LTMRS的过度兴奋性，进而导致SCI后的AT级疼痛。实际上，我们建议SCI转变 a-ltmrs陷入损伤附近的皮肤病的异肌编码伤害感受器，这是 转换部分是由于BDNF-TRKB上不可能的巨大空间和临时可塑性SCI 信号。拟议的研究由3个特定目标组成，将在转基因小鼠中完成，这将使我们能够 有选择地靶向表达TRKB的A-LTMR，完整的受试者和T10中度至重度挫伤之后 科学。 在SA 1中，使用Ex-Vivo Skin-neve，Vitro成年小鼠模型和脊柱切片的电生理研究 trkb :: Chr2小鼠中附着的背根将评估SCI对A-LTMRS招募，射击和 突触反应。我们还将研究Sci诱导的膨胀A-LTMRS的接受场，作为潜力 外围传入芽的结果（SA 2）。 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。 SA 3将雇用 行为测试以研究A-LTMRS在SCI后的AT级机械性异常性的发展中的作用 使用修改的位置逃生/厌恶范式，以及可调性和超声声音的度量 遵循机械和光学刺激。我们还将结合新颖的超敏运动检测 连续监测呼吸速率的传感器，这是一个可测量的交感神经诱导指标 也可能表明疼痛。 这项创新且与临床相关的研究将是第一个识别A-LTMR可塑性为中性的研究 SCI后AT级机械性异常尼亚的机制，该外围可塑性介导了转化 伤害感受器的皮肤触摸传入。从这项研究中获得的结果将增加我们的知识 科学后不良适应性感觉处理和疼痛的神经生理机制。