Central contributions to pathobiology of fibromyalgia

描述(申请人提供)：虽然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是未知的。CWP综合征，如纤维肌痛，是致残的，很难治疗。为了更全面地描述煤工尘肺的启动和驱动机制，我们开发了一种具有广泛的机械性痛敏的动物模型，该模型模仿煤工尘肺。反复肌肉注射酸到一块腓肠肌是一种独特的模型，因为有双侧机械性痛敏而不损伤周围组织，对侧痛觉过敏不是通过外周传入活动维持的。在双侧痛觉过敏的同时，1)双侧脊髓中转录因子CREB(cAMP反应元件结合蛋白)的磷酸化增加；2)酸诱导长时间肌肉疼痛后24小时，同侧背角神经元的感受野扩大到包括对侧肢体。我们假设，这些远离侮辱地点的双边事件反映了脑干的促进影响增加。在支持方面，来自头腹侧延髓内侧(RVM)的下行促进剂/通路介导或维持由关节内卡拉胶产生的继发性痛敏，以及与神经病理性疼痛和内脏炎症相关的痛敏。这些核团的脊髓投射是双侧的，这些延髓神经元的感受野广泛，包括对侧后肢。具体目的将确定在第一次或第二次注射酸性生理盐水期间或在诱导痛觉过敏后，局部麻醉剂或受体阻断RVM是否可以逆转双侧机械性痛觉过敏和反复肌肉内注射酸所产生的脊髓p-CREB增加，这是一种非炎症性广泛性肌肉疼痛的模型。我们还将确定第二次注射酸性生理盐水是否会增加RVM中谷氨酸的释放。这些研究将首次研究Q下行促进在肌肉损伤后的作用，并将进一步确定下行促进影响是否驱动脊髓变化。我们的专家认为，在肌肉损伤后发生的双侧痛觉过敏和双侧脊髓p-CREB的增加将通过在损伤时脊髓上阻断输入来防止，并在痛觉过敏发展后通过脊柱上阻断来逆转。这些研究还将首次确定RVM中谷氨酸的释放模式，以响应组织损伤。我们预计，第二次注射与痛觉过敏平行的酸性盐水后，谷氨酸会增加。如果是这样的话，这些数据将表明，利用谷氨酸对RVM的脊髓上影响对于双侧痛觉过敏和脊髓改变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。

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.