Role of Medullary Substance P in Acute and Persistent Nociception

髓质 P 在急性和持续性伤害感受中的作用

• 批准号: 8074480
• 负责人: DONNA L HAMMOND
• 金额: $ 56.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074480
• 关键词: Absence of pain sensation; Acute; Adrenergic Receptor; Afferent Neurons; Aminobutyric Acids; Analgesics; Arthritis; Behavioral; Brain; Brain Stem; Capsaicin; Cell Nucleus; Cells; Cerebrospinal Fluid; Chronic inflammatory pain; Cognitive; Coupled; Data; Dependence; Development; Dose; Emotional; Freund' s Adjuvant; Future; Glutamate Decarboxylase; Goals; Health; Hyperalgesia; Immunohistochemistry; Inflammatory; Injection of therapeutic agent; Injury; Knowledge; Label; Maintenance; Mechanics; Mediating; Microinjections; Molecular; Nature; Neurons; Neurotransmitters; Nociception; Norepinephrine; Outcome; Pain; Pathway interactions; Pattern; Peripheral; Persistent pain; Pharmacology; Pharmacotherapy; Physicians; Physiology; Play; Pontine structure; Population; Production; Property; Rattus; Regulation; Research; Research Personnel; Role; Series; Serotonin; Site; Slice; Soft Tissue Injuries; Spinal Cord; Spinal cord posterior horn; Staining method; Stains; Substance P; Substance P Receptor; Synapses; System; Tail; Tegmentum Mesencephali; Testing; Tetralones; Tetrodotoxin; Thermal Hyperalgesias; Time; Tracer; Tryptophan 5-monooxygenase; Withdrawal; Work; allodynia; central sensitization; chronic pain; extracellular; gamma-Aminobutyric Acid; innovation; insight; locus ceruleus structure; midbrain central gray substance; noradrenergic; patch clamp; postsynaptic; receptor; receptor internalization; research study; response

DESCRIPTION (provided by applicant): Our understanding of the mechanisms by which inflammatory injury leads to sustained changes in the function and properties of pain modulatory neurons in the rostral ventromedial medulla (RVM) remains rudimentary. Substance P (SubP) contributes to central sensitization after injury, yet surprisingly little is known about its role in the modulation of nociception by the RVM, where it also exists in high concentrations. Pilot data indicate that SubP has both antinociceptive and pronociceptive actions in the RVM in the uninjured state, but acts to mediate and sustain hyperalgesia after inflammatory injury. These data support four related hypotheses. 1) SubP exerts both pronociceptive and antinociceptive effects in the uninjured state by time-dependent activation of pain inhibitory and pain facilitatory bulbospinal pathways. Behavioral pharmacological studies will establish the dose-dependence and duration of SubP effects in the RVM of rats in the uninjured state, and confirm the role of neurokinin-1 (NK1) receptors. The bulbospinal pathways that mediate the effects of SubP will be determined by challenge with spinally-administered receptor antagonists before and at various times after SubP injection. 2) SubP is released in the RVM in response to inflammatory injury, where it plays a pronociceptive role in the development of hyperalgesia. The role of endogenous SubP released in the RVM after injury will be assessed by NK1 receptor internalization and by microinjection of NK receptor antagonists in the RVM of rats with acute and persistent hyperalgesia induced by complete Freund's adjuvant (CFA). 3) SubP effects reflect the expression of the NK1 receptor by specific types of RVM neurons, a pattern that may change after injury. Tract tracing and immunohistochemistry will identify RVM neurons that express NK1 receptors by their neurotransmitter content and projections to the spinal cord and DLPT. Subsequent studies will determine whether this expression changes after CFA, and will identify the types of RVM neurons in which NK1 receptor internalization (indicative of SubP release) occurs after injury. 4) SubP acts at specific populations of spinally-projecting RVM neurons and, in CFA-treated rats, enhances excitatory inputs to specific types of RVM neurons to mediate hyperalgesia. Whole-cell patch clamp recording from RVM neurons, coupled with retrograde labeling and immunohistochemical staining, will identify which types of RVM neurons express functional NK1 receptors and determine how the actions of SubP change after CFA. Extracellular recordings will determine the effect of SubP on ON, OFF and NEUTRAL cells and its role in the sensitization of these neurons after CFA. These studies will provide a mechanistic framework in which the antinociceptive and pronociceptive effects of SubP are related to specific populations of RVM neurons. These data in turn may enable us to identify their function (pro- vs antinociceptive). Collectively, these results will advance our understanding of the means and mechanisms by which peripheral inflammatory injury alters the responses and function of critical brainstem pain modulatory systems, and inform a more rationale development of centrally-acting analgesics for the relief of persistent pain. PUBLIC HEALTH RELEVANCE Persistent pain of an inflammatory nature, such as that associated with arthritis or soft tissue injury, exacts a significant financial, emotional and physical toll on its sufferers. The results of these studies will identify how persistent pain changes the function of brainstem pathways that are critically involved in the regulation of nociception and the production of analgesia. Insights gain from this work will guide the development of new, more effective pharmacotherapies or cognitive approaches for the relief of persistent pain.

描述（由申请人提供）：我们对炎症损伤导致头端腹内侧延髓（RVM）疼痛调节神经元的功能和特性持续变化的机制的理解仍然处于初级阶段。 P 物质 (SubP) 有助于损伤后中枢敏化，但令人惊讶的是，人们对其在 RVM 伤害感受调节中的作用知之甚少，而 RVM 中 P 物质也以高浓度存在。试验数据表明，在未受伤状态下，SubP 在 RVM 中具有抗伤害和促伤害作用，但在炎症损伤后起到介导和维持痛觉过敏的作用。这些数据支持四个相关假设。 1) SubP 在未受伤状态下通过时间依赖性激活疼痛抑制和疼痛促进球脊髓通路发挥促痛和抗痛作用。行为药理学研究将确定未受伤状态下大鼠 RVM 中 SubP 作用的剂量依赖性和持续时间，并确认神经激肽-1 (NK1) 受体的作用。介导 SubP 作用的球脊髓通路将通过在注射 SubP 之前和之后的不同时间用脊髓施用的受体拮抗剂激发来确定。 2) SubP 在 RVM 中释放以响应炎症损伤，在痛觉过敏的发展中发挥促伤害作用。损伤后 RVM 中释放的内源性 SubP 的作用将通过 NK1 受体内化和通过在由完全弗氏佐剂 (CFA) 诱导的急性和持续性痛觉过敏的大鼠的 RVM 中显微注射 NK 受体拮抗剂来评估。 3) SubP效应反映了特定类型的RVM神经元的NK1受体表达，这种模式在损伤后可能会改变。纤维束追踪和免疫组织化学将通过神经递质含量以及对脊髓和 DLPT 的投射来识别表达 NK1 受体的 RVM 神经元。后续研究将确定这种表达在 CFA 后是否发生变化，并将确定损伤后发生 NK1 受体内化（指示 SubP 释放）的 RVM 神经元的类型。 4) SubP作用于脊髓投射的RVM神经元的特定群体，并且在CFA治疗的大鼠中，增强对特定类型的RVM神经元的兴奋性输入以介导痛觉过敏。 RVM 神经元的全细胞膜片钳记录，加上逆行标记和免疫组织化学染色，将识别哪些类型的 RVM 神经元表达功能性 NK1 受体，并确定 CFA 后 SubP 的作用如何变化。细胞外记录将确定 SubP 对 ON、OFF 和 NEUTRAL 细胞的影响及其在 CFA 后这些神经元敏化中的作用。这些研究将提供一个机制框架，其中 SubP 的抗伤害和伤害感受作用与特定的 RVM 神经元群体相关。这些数据反过来可以使我们识别它们的功能（促痛与抗痛）。总的来说，这些结果将增进我们对外周炎症损伤改变关键脑干疼痛调节系统的反应和功能的方式和机制的理解，并为缓解持续性疼痛的中枢镇痛药的更合理的开发提供信息。 公共卫生相关性 炎症性质的持续疼痛，例如与关节炎或软组织损伤相关的疼痛，会给患者造成重大的经济、情感和身体损失。这些研究的结果将确定持续性疼痛如何改变脑干通路的功能，而脑干通路对于伤害感受的调节和镇痛的产生至关重要。从这项工作中获得的见解将指导开发新的、更有效的药物疗法或认知方法来缓解持续性疼痛。