Proprioceptive mechanisms underlying post-spinal manipulation response in an NGF-induced low back pain model

NGF 诱导的腰痛模型中脊柱操作后反应的本体感觉机制

• 批准号: 9805686
• 负责人: William Ray Reed
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805686
• 关键词: BAG2 gene; Behavioral Assay; Biological; Biological Factors; Biomechanics; Characteristics; Chemosensitization; Chronic low back pain; Classification; Clinical; Clinical Practice Guideline; Data; Devices; Environment; Facilities and Administrative Costs; Fiber; Guidelines; Health; Hyperalgesia; Inflammation; Injections; Injury; Intervention; Knowledge; Laboratories; Ligaments; Light; Low Back Pain; Mechanics; Mechanoreceptors; Muscle; Muscle Spindles; Muscle Tonus; Nerve Growth Factors; Nociceptors; Pain; Pain management; Peripheral nerve injury; Physicians; Physiological; Pilot Projects; Posterior Horn Cells; Pre-Clinical Model; Productivity; Property; Sensory; Site; Skeletal Muscle; Spinal; Spinal Manipulation; Stimulus; Strategic Planning; Stretching; Structure; Therapeutic; Thermal Hyperalgesias; Time; Tissues; United States; United States National Institutes of Health; Visit; Work; base; capsule; chemosensitizing agent; clinically relevant; cost; disability; economic impact; in vivo; mechanical force; neurophysiology; neurotrophic factor; opioid epidemic; pain model; pre-clinical; prescription opioid; response; soft tissue; treatment optimization; viscoelasticity

Abstract. Low back pain (LBP) is a major health problem in the United States costing annually over $50 billion in treatment-related costs and $100 billion in indirect costs (i.e. lost productivity). This national health crisis is further compounded by a recent over-reliance on prescription opioids for therapeutic pain management. High velocity low amplitude spinal manipulation (HVLA-SM) is a non-pharmacological LBP approach recommended by a majority of clinical practice guidelines. However, a lack of knowledge concerning underlying neurophysiological mechanisms hinders wider clinical acceptance, usage, and optimization of this therapeutic approach. Proposed mechanisms of HVLA-SM efficacy include changes in muscle spindle sensitivity related to rapid stretch-induced stimulation of mechanoreceptors in muscle and/or other trunk tissues. Previous work in our lab has shed light on the relationship between the mechanical characteristics of HVLA-SM (thrust duration, thrust amplitude, thrust rate, preload magnitude & duration, and thrust contact site) and trunk muscle spindle afferent responsiveness in non-chemosensitized environments. Recently pilot studies using commercially available HVLA-SM devices with extremely short thrust durations of 2-3ms revealed a dichotomy among post-HVLA-SM return to baseline muscle spindle discharge. Distinct subpopulations of spindle afferents returned to baseline discharge post-HVLA-SM relatively rapidly (<2s), while others required substantially longer periods (>10s), which far outlasted the mechanical stimulus of HVLA-SM. The biological and/or biomechanical factors responsible for this post-HVLA-SM response dichotomy, as well as whether or not clinically relevant tissue chemosensitization acts to maximize these dichotomous post-HVLA-SM responses is currently unknown. A recently developed preclinical LBP model has been established using a translationally relevant pain molecule, nerve growth factor (NGF). NGF is a neurotrophin associated with pain which is naturally upregulated after muscle damage, inflammation, and/or peripheral nerve injury. Injection of NGF into deep trunk musculature creates persistent (days/weeks), localized trunk hyperalgesia by sensitizing skeletal muscle nociceptors and producing marked spinal dorsal horn neuron hyperexcitability; both of which are thought to be key components of LBP chronicity. This proposal will characterize post-HVLA-SM muscle spindle response based on intrafusal fiber classification, HVLA-SM thrust duration (2-3ms vs 100ms), and HVLA-SM peak biomechanical forces reaching deep spinal tissues (multifidus muscle) in control and trunk chemosensitized (NGF-induced LBP) environments in order to reveal neurophysiological mechanisms underlying spinal manipulation and to establish another preclinical NGF-induced LBP model so as to better inform and/or optimize this non-pharmacological approach to LBP.

抽象。 下背痛（LBP）是美国的一个主要健康问题，每年花费超过500亿美元的治疗相关费用和1000亿美元的间接费用（即生产力损失）。最近过度依赖处方阿片类药物进行治疗性疼痛管理，进一步加剧了这一国家健康危机。高速低幅度脊柱推拿（HVLA-SM）是大多数临床实践指南推荐的非药物LBP方法。然而，缺乏关于潜在神经生理机制的知识阻碍了这种治疗方法的更广泛的临床接受、使用和优化。提出的HVLA-SM功效的机制包括与肌肉和/或其他躯干组织中的机械感受器的快速牵张诱导的刺激相关的肌梭敏感性的变化。我们实验室以前的工作揭示了HVLA-SM的机械特性（推力持续时间，推力幅度，推力率，预负荷大小和持续时间，推力接触部位）和躯干肌梭传入反应在非化学致敏环境之间的关系。最近，使用具有2- 3 ms的极短推力持续时间的市售HVLA-SM装置的初步研究揭示了HVLA-SM后恢复到基线肌梭放电之间的二分法。不同的纺锤体传入亚群在HVLA-SM后相对快速地（<2s）返回到基线放电，而其他亚群需要实质上更长的时间（> 10 s），这远远超过HVLA-SM的机械刺激。目前尚不清楚导致这种HVLA-SM后反应二分法的生物学和/或生物力学因素，以及临床相关组织化学增敏是否起到使这些二分法的HVLA-SM后反应最大化的作用。最近开发的临床前LBP模型已建立使用神经相关的疼痛分子，神经生长因子（NGF）。NGF是一种与疼痛相关的神经营养因子，其在肌肉损伤、炎症和/或外周神经损伤后自然上调。将NGF注射到躯干深部肌肉组织中，通过使骨骼肌伤害感受器敏感并产生显著的脊髓背角神经元过度兴奋，产生持续（数天/周）的局部躯干痛觉过敏;这两者被认为是LBP慢性化的关键组成部分。该提案将根据梭内纤维分类、HVLA-SM推力持续时间和肌梭内肌纤维类型来表征HVLA-SM后肌梭反应。（2-3ms vs 100ms），和HVLA-SM达到深层脊柱组织的峰值生物力学力（多裂肌）对照组和躯干化学敏化组（NGF诱导的LBP）环境，以揭示脊柱操作的神经生理学机制，并建立另一种临床前NGF-诱导的LBP模型，以便更好地告知和/或优化LBP的这种非药理学方法。