Understanding multisensory hypersensitivity in chronic pain states

项目摘要 许多慢性疼痛患者抱怨对多种感觉的异常敏感性 形态，包括光、声音和气味。潜在的神经基础仍然是一个谜 这些说法往往被怀疑，因为感官敏锐度本身并不 在初级感觉通路中也没有增强的处理。中央 这项提议的论点是，脑干疼痛调节系统的功能障碍， 被认为有助于在这些条件下的疼痛，也可能在多感觉中发挥作用。 超敏反应。这一假设是基于我们意外的观察， 延髓头端腹内侧区的疼痛调节神经元，是一个重要的 脑干疼痛调节系统对光有反应在三个特定的目标使用单细胞 记录方法在大鼠中，我们将充分表征RVM对光的反应， 刺激-反应函数并建立相关频谱。我们还将确定 在偏头痛动物模型中这些神经元的光反应性是否增强 头痛（其中光敏性是有据可查的）或处于持续性炎症状态。 最后，我们将从更高的角度研究光响应性的“自上而下”调制。 已知有助于应激诱发的痛觉过敏的大脑结构， 内分泌、自主神经和行为反应。现时的建议 将电生理学和行为学方法结合起来， 参与疼痛调节系统，有效地将视觉刺激转化为躯体刺激， 感觉，产生不适和厌恶。这些研究将提供基本的 深入了解多感觉超敏反应的神经生物学机制，信息 对于开发更合适的治疗偏头痛和其他慢性疼痛的方法至关重要 紊乱

PROJECT SUMMARY Many chronic pain patients complain of abnormal sensitivity to multiple sensory modalities, including light, sound, and smell. The underlying neural basis remains a puzzle and these claims are often viewed with suspicion, since sensory acuity per se is not enhanced, nor is there amplified processing in primary sensory pathways. The central thesis of this proposal is that dysfunction of brainstem pain-modulating systems, already thought to contribute to pain in these conditions, is also likely to play a role in multisensory hypersensitivity. This hypothesis is based on our unexpected observation that a subset of pain-modulating neurons in the rostral ventromedial medulla, the final output of an important brainstem pain-modulating system, respond to light. In three Specific Aims using single-cell recording approaches in rat, we will fully characterize the RVM response to light, generating stimulus-response functions and establishing the relevant spectrum. We will also determine whether photoresponsiveness of these neurons is enhanced in an animal model of migraine headache (where photosensitivity is well documented) or in a persistent inflammatory state. Finally, we will investigate “top-down” modulation of photoresponsiveness from a higher brain structure known to contribute to stress-induced hyperalgesia and implicated in endocrine, autonomic, and behavioral responses to mild stress. The present proposal brings together electrophysiological and behavioral approaches to determine how light engages pain-modulating systems, effectively converting a visual stimulus to a somatic sensation, producing discomfort and aversion. These studies will provide fundamental insights into the neurobiological mechanisms of multisensory hypersensitivity, information critical to developing more appropriate treatments for migraine and other chronic pain disorders.