Rodent Behavioral Model of Ongoing Headache Pain

描述（由申请人提供）：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“自发”或持续疼痛的分析，而不是触觉或热超敏反应。特别是头痛领域，多年来一直受到没有行为分析的严重限制。目前的证据支持偏头痛和其他头痛是由脑膜末端的感觉神经激活引起的这一观点。因此，实验诱导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脑膜（硬脑膜）刺激在清醒的大鼠中引起面部异常痛，首次提供了动物头痛的行为模型。我们现在提出，我们认为这是头痛研究的进一步突破：对大鼠硬脑膜化学刺激后“自发”行为变化的新观察。核心发现是正常探索行为的抑制，以及伴随的“休息”行为或安静清醒的数量的增加。这可能被认为是抑制先天行为/运动活动的更普遍现象的一个例子，它已被用作评估自发性疼痛的方法。硬脑膜刺激还引起了短暂的同侧面部“梳理”或摩擦，主要是用后爪而不是前爪。至关重要的是，这些行为改变被曲坦类药物预处理部分阻断。我们现在建议通过在大鼠中更详细地表征该模型来追求这些发现，然后使用相同的方法在小鼠中也建立该模型。在大鼠身上的实验将：1)评估该模型的剂量-反应曲线，以找到足以产生强烈行为反应的最低浓度的炎症介质；2)测量硬脑膜应用药物的脑脊液水平，以研究通过硬脑膜的扩散量；3)寻求脑电图谱变化的初步发现，包括theta活动的增加，与安静清醒时“休息”次数的增加相关。在接受硬脑膜刺激的大鼠中。对小鼠的研究将比较不同菌株的伤害性反应和曲坦类药物敏感性，并确定高反应菌株和低反应菌株的顺序是否与之前在其他疼痛模型中发现的不同。这将为未来的研究开辟一条途径，以确定对硬脑膜刺激反应和曲坦类药物敏感性的遗传决定因素。除了具有与刺激诱发的超敏反应相反的“自发”疼痛的潜在关联的意义之外，该模型还有一个优点，即它避免了应用von Frey测试的必要性，这是特别困难的

DESCRIPTION (provided by applicant): 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.