Rodent Behavioral Model of Ongoing Headache Pain

项目摘要 疼痛领域一直需要开发更好的方法来评估动物的疼痛，特别是测试。 “自发”或持续的疼痛，而不是触觉或热过敏。中的头痛领域 特别是多年来一直遭受着没有行为测试的严重限制。现有证据 现在支持偏头痛和其他头痛是由感觉神经激活引起的观点 最后出现在脑膜上。因此，实验诱导的这些脑膜神经末梢的激活 已被用于研究头痛的机制。一项重大突破是证明了化学物质 脑膜(硬膜)刺激引起清醒大鼠面部痛觉异常，首次提供了一种行为反应。 动物头痛模型。我们现在提议寻求我们认为是进一步突破的 头痛研究：化学刺激后“自发”行为改变的新观察 大鼠的硬脑膜。核心发现是对正常探索行为的抑制，以及伴随而来的 增加“休息”行为或安静清醒的数量。这可以被认为是 一种更普遍的抑制先天行为/运动活动的现象，曾被用作 评估自发性疼痛的方法。硬脑膜刺激也引起了同侧短暂的起始期。 面部“梳理”或摩擦，主要是用后爪，而不是前爪。关键的是，这些 曲普坦可部分阻断动物的行为改变。我们现在建议继续调查这些发现。 通过在老鼠身上更详细地描述这种模型，然后使用相同的方法也建立了这种模型 以小鼠为模型。在大鼠体内的实验将：1)评估该模型的剂量-反应曲线，以便找出 足以产生强健行为的最低浓度的应用炎症介质 反应，2)测量长期应用药物的脑脊液水平，以调查通过 硬脑膜，以及3)脑电频谱变化的初步发现，包括theta的增加 在接受硬脑膜注射的大鼠中，活动与安静觉醒次数的增加有关 刺激。对小鼠的研究将比较不同菌株的伤害性反应和曲普坦。 敏感性，并确定高反应菌株与低反应菌株的顺序是否与发现的不同 其他疼痛模型的前情提要。这将为未来识别基因的研究开辟一条途径 硬脑膜刺激反应和曲普坦敏感性的决定因素。除了拥有一个 与刺激诱发的高敏感症相反，这个模型也有“自发”疼痛的潜在相关性 优点是它避免了应用von Frey测试的必要性，而von Frey测试在 老鼠。将进行补充性研究，以检查神经激活的解剖标志(FOS和 Perk)将浅层或深层背角板层以及其他中央区域的激活与 行为反应的大小。

Project Summary The pain field has had an ongoing need to develop better ways of assessing pain in animals, especially assays of "spontaneous" or ongoing pain as opposed to tactile or thermal hypersensitivity. The headache field in particular for many years suffered from the severe limitation of having no behavioral assay. Current evidence now supports the idea that migraine and other headaches result from the activation of the sensory nerves that end in the meninges. Consequently, experimentally induced activation of these meningeal nerve endings has been used to investigate headache mechanisms. A major breakthrough was the demonstration that chemical meningeal (dural) stimulation induced facial allodynia in awake rats, providing for the first time a behavioral model of headache in animals. We now propose to pursue what we believe is a further breakthrough for the study of headache: a new observation of a change in "spontaneous" behavior following chemical stimulation of the dura in rats. The core finding is a suppression of the normal exploratory behavior, and a concomitant increase in the amount of "resting' behavior or quiet wakefulness. This may be considered an example of the more general phenomenon of suppression of an innate behavior/locomotor activity, which has been used as an approach for assessing spontaneous pain. The dural stimulus also induced a brief initial period of ipsilateral facial "grooming" or rubbing that was done primarily with the hindpaw rather than the forepaw. Critically, these behavioral changes were partially blocked by triptan pre-treatment. We now propose to pursue these findings by characterizing this model in more detail in the rat, and by then using the same methods to also establish this model in mice. Experiments in the rat will: 1) evaluate the dose-response curve for this model, in order to find the lowest concentration of applied inflammatory mediators that is sufficient for producing a robust behavioral response, 2) measure CSF levels of the durally applied agents to investigate the amount of diffusion through the dura, and 3) pursue preliminary findings of changes in the EEG spectrum, consisting of an increase in theta activity, correlated with the bouts of increased "resting" of quiet wakefulness, in the rats that received the dural stimulus. Studies in mice will compare different strains for both their nociceptive response and triptan sensitivity, and determine whether the order of high- vs low-responding strains differs from that found previously for other pain models. This will open an avenue for future studies into identifying genetic determinants of the response to dural stimulation and triptan sensitivity. Besides the significance of having a potential correlate of "spontaneous" pain as opposed to stimulus-evoked hypersensitivity, this model also has the advantage that it avoids the necessity for applying von Frey testing, which is especially difficult in the mouse. Complementary studies will be carried out to examine anatomical markers of neural activation (fos and pERK) to correlate activation in superficial or deep dorsal horn laminae, as well as other central regions, with the magnitude of the behavioral response.