Central contributions to pathobiology of fibromyalgia

对纤维肌痛病理学的重要贡献

• 批准号: 7485041
• 负责人: KATHLEEN A SLUKA
• 金额: $ 30.15万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485041
• 关键词: Acids; Address; Animal Model; Animals; Bilateral; Brain Stem; Capsaicin; Carrageenan; Cell Nucleus; Chronic; Clinical; Condition; Contralateral; Cutaneous; Cyclic AMP-Responsive DNA-Binding Protein; Data; Depth; Development; Distant; Etiology; Event; Exhibits; Fibromyalgia; Gastrocnemius Muscle; Generations; Glutamates; Goals; Hindlimb; Hyperalgesia; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intramuscular; Intramuscular Injections; Ipsilateral; Knowledge; Lead; Limb structure; Local Anesthetics; Maintenance; Mechanics; Medial; Mediating; Modeling; Muscle; Musculoskeletal Pain; Myalgia; Myositis; N-Methyl-D-Aspartate Receptors; Neurons; Pain; Pathology; Pathway interactions; Pattern; Peripheral; Phosphorylation; Population; Posterior Horn Cells; Qualifying; Research Personnel; Role; Saline; Secondary Hyperalgesias; Site; Skin; Spinal; Spinal Cord; Stimulus; Syndrome; Testing; Time; Tissues; United States; Visceral; Withdrawal; day; novel therapeutics; nucleus reticularis; painful neuropathy; prevent; programs; raphe nucleus magnus; receptive field; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): Although 10-15% of the United States population suffers from chronic widespread musculoskeletal pain (CWP), the etiology of these conditions is virtually unknown. CWP syndromes, such as fibromyalgia, are disabling and difficult to treat. To more fully characterize the mechanisms that initiate and drive CWP, we developed an animal model with widespread mechanical hyperalgesia that mimics CWP. Repeated intramuscular injections of acid into one gastrocnemius muscle is a unique model since there is bilateral mechanical hyperalgesia without peripheral tissue damage, and the contralateral hyperalgesia is not maintained by peripheral afferent activity. In parallel to the bilateral hyperalgesia, 1) there are bilateral increases in the spinal cord for the phosphorylation of the transcription factor, CREB (cAMP responsive element binding protein); 24 h following induction of long-lasting muscle pain with acid, and 2) ipsilateral dorsal horn neurons show an expansion of their receptive fields to include the contralateral limb. We posit that these bilateral events distant from the site of insult reflect increased facilitatory influences from the brainstem. In support, descending facilitator/ pathways from the rostroventral medial medulla (RVM) mediate or maintain secondary hyperalgesia produced by intra-articular carrageenan, and the hyperalgesia associated with neuropathic pain and visceral inflammation. The spinal projections from these nuclei are bilateral, and receptive fields of these medullary neurons are widespread and include the contralateral hind limb. The Specific Aims will determine if local anesthetic or receptor blockade of the RVM during the first or second injection of acidic saline prevents, or after induction of hyperalgesia reverses the bilateral mechanical hyperalgesia and spinal increases in p-CREB produced by repeated intramuscular acid injection, a model of non-inflammatory widespread muscle pain. We will also determine if there is an increased release of glutamate in the RVM in response to the second injection of acidic saline. These studies will be the first to examine the role of Q descending facilitation following muscle insult and will further determine if descending facilitatory influences drive the spinal cord changes. We expert that the bilateral hyperalgesia and bilateral spinal increases in p-CREB that occur after muscle insult will be prevented by supraspinal blockade of input at the time of insult, and reversed by supraspinal blockade after development of hyperalgesia. These studies will also be the first to determine the release pattern for glutamate in the RVM in response to tissue injury. We expect an increase in glutamate in response to the second injection of acidic saline that parallels the hyperalgesia. If so, these data would suggest that supraspinal influences in the RVM utilizing glutamate are critical for the generation and the maintenance of bilateral hyperalgesia and spinal cord changes. A better understanding of the pathobiological mechanisms underlying musculoskeletal pain conditions may lead to the development of novel therapeutic approaches for its treatment.

描述（由申请人提供）：尽管 10-15% 的美国人口患有慢性广泛性肌肉骨骼疼痛 (CWP)，但这些病症的病因实际上尚不清楚。 CWP 综合征，例如纤维肌痛，会致残且难以治疗。为了更全面地表征启动和驱动 CWP 的机制，我们开发了一种模仿 CWP 的具有广泛机械痛觉过敏的动物模型。向一侧腓肠肌重复肌内注射酸是一种独特的模型，因为存在双侧机械痛觉过敏而没有外周组织损伤，并且对侧痛觉过敏不是由外周传入活动维持的。与双侧痛觉过敏并行的是，1）脊髓中转录因子 CREB（cAMP 反应元件结合蛋白）磷酸化的双侧增加；用酸诱导持久肌肉疼痛 24 小时后，2) 同侧背角神经元显示其感受野扩大，包括对侧肢体。我们假设这些远离损伤部位的双侧事件反映了脑干的促进性影响的增加。作为支持，来自前腹内侧髓质（RVM）的下行促进器/通路介导或维持关节内角叉菜胶产生的继发性痛觉过敏，以及与神经性疼痛和内脏炎症相关的痛觉过敏。这些核的脊柱投射是双侧的，这些髓质神经元的感受野很广泛，包括对侧后肢。具体目标将确定在第一次或第二次注射酸性盐水期间对 RVM 进行局部麻醉或受体阻断是否可以预防或在诱导痛觉过敏后逆转重复肌内酸注射产生的双侧机械痛觉过敏和 p-CREB ​​脊髓增加，这是一种非炎症性广泛肌肉疼痛的模型。我们还将确定 RVM 中谷氨酸的释放是否因第二次注射酸性盐水而增加。这些研究将首次检验肌肉损伤后 Q 下降易化的作用，并将进一步确定下降易化影响是否驱动脊髓变化。我们专家认为，肌肉损伤后发生的双侧痛觉过敏和双侧脊髓 p-CREB ​​增加可以通过损伤时的脊髓上阻滞来预防，并在出现痛觉过敏后通过脊髓上阻滞来逆转。这些研究也将首次确定 RVM 中谷氨酸响应组织损伤的释放模式。我们预计第二次注射酸性盐水时谷氨酸会增加，这与痛觉过敏相似。如果是这样，这些数据表明，利用谷氨酸对 RVM 的脊髓上影响对于双侧痛觉过敏和脊髓变化的产生和维持至关重要。更好地了解肌肉骨骼疼痛的病理生物学机制可能会导致开发新的治疗方法。