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）：我们对炎症性损伤导致疼痛调节神经元功能和特性的机制的理解仍然是基本的。物质p（传票）有助于损伤后中央敏化，但令人惊讶的是，它在RVM对伤害感受的调节中的作用鲜为人知，在该调节中，它也以高浓度存在。试验数据表明，在不受影响的状态下，Subp在RVM中具有抗伤害感受感和引起感受感，但是在炎症损伤后介导和维持痛觉过敏。这些数据支持四个相关的假设。 1）传票通过时间依赖性抑制性抑制性和疼痛促进性球囊途径在不受影响的状态下施加引起感受感和抗伤害感受效应。行为药理学研究将建立在未受害状态下大鼠RVM中传染性效应的剂量依赖性和持续时间，并确认Neurokinin-1（NK1）受体的作用。介导传播作用的球囊途径将取决于传票注射后的不同时间和在不同时间的旋转剂量受体拮抗剂的挑战。 2）在RVM中释放了SubP，以应对炎症性损伤，在炎症性损伤中起着引起感人的作用。损伤后RVM中释放的内源性传播的作用将通过NK1受体内在化和通过急性和持久性的Hypergersia在大鼠RVM中对NK受体拮抗剂的显微注射来评估。 3）传票效应反映了特定类型的RVM神经元的NK1受体的表达，这种模式可能会在受伤后发生变化。道追踪和免疫组织化学将鉴定RVM神经元通过其神经递质的含量和投影向脊髓和DLPT表达NK1受体。随后的研究将确定CFA后这种表达是否发生变化，并确定NK1受体内在化（表明SubP释放的指示）在受伤后发生的RVM神经元的类型。 4）子P在旋转旋转的RVM神经元的特定群体中起作用，在经CFA处理的大鼠中，可以增强对特定类型的RVM神经元的兴奋性输入，以介导Hypergeria。 RVM神经元的全细胞贴片夹记录，再加上逆行标记和免疫组织化学染色，将确定哪种类型的RVM神经元表达功能性NK1受体，并确定SubP后CFA后的作用如何变化。细胞外记录将确定Subp ON，OFF和中性细胞的影响及其在CFA后这些神经元敏化中的作用。这些研究将提供一个机械框架，在该框架中，Subp的抗伤害感受和关注性效应与RVM神经元的特定种群有关。这些数据反过来可能使我们能够识别其功能（对抗伤害感受）。总的来说，这些结果将促进我们对外周炎症性损伤改变关键脑干疼痛调节系统的反应和功能的手段和机制的理解，并为中心作用的止痛药的更加理由发展，以缓解持续性疼痛。 公共卫生相关性的炎症性质持续性疼痛，例如与关节炎或软组织损伤相关的疼痛，对其患者造成了重大的财务，情感和身体伤害。这些研究的结果将确定持续性疼痛如何改变与伤害感受和镇痛产生的严重涉及的脑干途径的功能。从这项工作中获得的见解将指导开发新的，更有效的药物治疗或认知方法，以缓解持续性疼痛。