Understanding multisensory hypersensitivity in chronic pain states

项目总结 许多慢性疼痛患者抱怨对多种感官异常敏感。 形态，包括光、声音和气味。潜在的神经基础仍然是一个谜。 这些说法经常受到怀疑，因为感官敏锐度本身并不是 增强，在初级感觉通路中也没有放大的处理。中环 这项建议的论点是脑干疼痛调制系统的功能障碍，已经 被认为在这些情况下会导致疼痛，也可能在多感官中发挥作用 过敏症。这一假设是基于我们出人意料的观察结果，即 在延髓头端腹内侧，痛觉调制神经元的最终输出是一个重要的 脑干疼痛调节系统，对光做出反应。在三个特定的目标中使用单细胞 在大鼠中记录方法，我们将充分表征RVM对光的反应，产生 刺激-反应函数，并建立相应的谱。我们还将确定 偏头痛动物模型中这些神经元的光反应是否增强 头痛(对光敏有充分的记载)或持续的炎症状态。 最后，我们将从更高的角度研究光响应性的自上而下的调制 已知的大脑结构有助于应激诱导的痛觉过敏，并与 对轻度压力的内分泌、自主神经和行为反应。目前的建议 将电生理和行为方法结合起来，以确定光线 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 对多感觉过敏、信息的神经生物学机制的洞察 对于开发更适合偏头痛和其他慢性疼痛的治疗方法至关重要 精神错乱。

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.