Central contributions to pathobiology of fibromyalgia

描述（由申请人提供）：虽然10-15%的美国人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，难以治疗。为了更充分地描述启动和驱动CWP的机制，我们开发了一种具有广泛机械痛觉过敏的动物模型来模拟CWP。向一侧腓肠肌肌内反复注射酸是一种独特的模型，因为存在双侧机械性痛觉过敏而没有外周组织损伤，并且对侧痛觉过敏不受外周传入活动的维持。与双侧痛觉过敏平行，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；在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接受野的扩张，包括对侧肢体。我们假设，这些远离侮辱部位的双侧事件反映了脑干增加的促进作用。作为支持，来自前腹侧内侧髓质（RVM）的下行促进通路介导或维持由关节内卡拉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。来自这些核的脊髓投射是双侧的，这些髓质神经元的接受野分布广泛，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局部麻醉或受体阻断RVM是否可以预防，或在诱导痛觉过敏后逆转双侧机械性痛觉过敏和反复肌内酸注射产生的脊柱p-CREB增加，这是一种非炎症性广泛肌肉疼痛模型。我们还将确定在第二次注射酸性盐水后，RVM中谷氨酸的释放是否增加。这些研究将首次检验肌肉损伤后Q下降促进的作用，并将进一步确定下降促进是否会驱动脊髓变化。我们认为，肌肉损伤后发生的双侧痛觉过敏和双侧脊柱p-CREB升高，在损伤时通过椎上阻滞输入可以预防，在痛觉过敏发生后通过椎上阻滞可以逆转。这些研究也将首次确定谷氨酸在RVM中对组织损伤的释放模式。我们期望在第二次注射与痛觉过敏平行的酸性生理盐水后谷氨酸增加。如果是这样，这些数据表明，利用谷氨酸的RVM的椎上影响对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.