Migraine headache and central pain facilitating systems

尽管偏头痛在普通人群中的患病率很高，但我们对其潜在机制的了解仍然不完整。关于周围神经或神经血管机制的各种理论已经提出，但到目前为止，这些理论都没有得到确凿的实验支持。另一种说法是，偏头痛是由大脑本身的“中枢发电机”触发的，或者至少是维持的。我们最近发现，头端延髓腹内侧区(RVM)是一个已知在痛觉调制中发挥作用的区域，它与偏头痛动物模型硬脑膜炎症后的行为过敏有关。这项拟议的研究将测试RVM神经元的特定群体在该模型中的作用，该群体被称为“on-cell”。为此，我们将记录已识别的RVM疼痛调节的活动 在硬脑膜炎症之前和之后的神经细胞，并确定细胞上是否通过使用药理学工具操纵该细胞和其他RVM细胞类别的活动来调节观察到的行为变化。 这项提案中描述的实验将试图通过将偏头痛的“中枢敏感化”的概念扩展到脑干调节系统来描绘更完整的偏头痛疼痛理论。我们期望为偏头痛疼痛的“中枢生成器”这一观点找到重要的支持。这个想法很有吸引力，因为中枢功能障碍可能会解释偏头痛的多种触发因素，以及一系列相关症状，包括恶心和对光和声音的厌恶。

Despite the high prevalence of migraine in the general population, our understanding of the underlying mechanisms remains incomplete. A variety of theories focused on peripheral neural or neurovascular mechanisms have been put forward, but none of these has so far received conclusive experimental support. An alternative proposal is that migraine is triggered, or at least maintained, by a “central generator” in the brain itself. We recently showed that the rostral ventromedial medulla (RVM), a region with a well documented role in pain modulation, contributes to behavioral hypersensitivity following dural inflammation, an animal model of migraine headache. The proposed studies will test the role of specific population of RVM neurons, termed “ON-cells”, in this model. To accomplish this, we will record activity of identified RVM painmodulating neurons before and after dural inflammation and determine whether ON-cell mediate observed behavioral changes by manipulating the activity of this and other RVM cell classes using pharmacological tools. The experiments described in this proposal will attempt to delineate a more complete theory of migraine headache pain by extending the idea of “central sensitization” in migraine headache to brainstem modulatory systems. We expect to find important support for the idea of a “central generator” in migraine headache pain. This idea is attractive because a central dysfunction could potentially explain the multiple triggers for migraine attached, as well as the range of associated symptoms, including nausea and aversion to light and sound.