Central contributions to pathobiology of fibromyalgia

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），但这些疾病的病因几乎未知。CWP综合征，如纤维肌痛，是致残和难以治疗的。为了更充分地表征启动和驱动CWP的机制，我们开发了一种动物模型，广泛的机械痛觉过敏，模仿CWP。重复肌肉注射酸到一个腓肠肌是一个独特的模型，因为有双边的机械痛觉过敏没有外周组织损伤，和对侧的痛觉过敏不维持外周传入活动。与双侧痛觉过敏平行，1）在用酸诱导持久性肌肉疼痛后24 h，脊髓中存在转录因子CREB（cAMP反应元件结合蛋白）磷酸化的双侧增加，以及2）同侧背角神经元显示出其感受野的扩展以包括对侧肢体。我们认为，这些双边事件远离侮辱的网站反映了从脑干促进的影响增加。作为支持，来自延髓吻腹侧内侧（RVM）的下行促进剂/通路介导或维持由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。这些核团的脊髓投射是双侧的，这些髓神经元的感受野广泛分布，包括对侧后肢。特定目的将确定在第一次或第二次注射酸性生理盐水期间RVM的局部麻醉或受体阻断是否预防或在诱导痛觉过敏后逆转双侧机械性痛觉过敏和由重复肌内酸注射产生的p-CREB脊髓增加，这是一种非炎性广泛性肌肉疼痛模型。我们还将确定是否有一个增加释放谷氨酸的RVM响应于第二次注射的酸性盐水。这些研究将是第一个检查肌肉损伤后Q下降易化的作用，并将进一步确定是否下降易化影响驱动脊髓的变化。我们认为，在肌肉损伤后发生的双侧痛觉过敏和双侧脊髓p-CREB增加将通过在损伤时脊髓上阻断输入来防止，并且在痛觉过敏发生后通过脊髓上阻断来逆转。这些研究也将是第一个确定响应组织损伤的RVM中谷氨酸释放模式的研究。我们预计谷氨酸盐的增加是对第二次注射酸性盐水的反应，这与痛觉过敏平行。如果是这样的话，这些数据表明，在RVM利用谷氨酸的脊髓上的影响是至关重要的产生和维持双边痛觉过敏和脊髓的变化。更好地了解肌肉骨骼疼痛条件下的病理生物学机制可能会导致其治疗的新的治疗方法的发展。

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.