Rodent Behavioral Model of Ongoing Headache Pain

持续性头痛的啮齿动物行为模型

• 批准号: 8734500
• 负责人: Andrew Mark Strassman
• 金额: $ 21.53万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734500
• 关键词: Acclimatization; Acetaminophen; Animals; Behavior; Behavioral; Behavioral Assay; Behavioral Model; Biological Assay; Cannulas; Cephalic; Chemical Stimulation; Chemicals; Circadian Rhythms; Core Facility; Development; Diffusion; Dose; Dura Mater; Electrodes; Electroencephalography; Environment; Exploratory Behavior; Face; Future; Genetic Determinism; Grooming; Headache; Hypersensitivity; Inflammation Mediators; Instinct; Ipsilateral; Knock-out; Laboratories; Measures; Meningeal; Meningeal Nerve; Meninges; Methods; Migraine; Modeling; Molecular; Molecular Genetics; Motor; Motor Activity; Mus; Nerve Endings; Operative Surgical Procedures; Pain; Peripheral; Pharmaceutical Preparations; Phonophobias; Photophobia; Publishing; Rattus; Reflex action; Relative (related person); Research; Research Personnel; Rest; Rodent; Sensory Nerve Endings; Site; Stimulus; Tactile; Testing; Time; Tissues; Variant; Wakefulness; Withdrawal; allodynia; awake; behavior test; clinical efficacy; dorsal horn; follow-up; implantation; nociceptive response; public health relevance; relating to nervous system; research study; response; spontaneous pain; triptans; zolmitriptan

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.

描述（由申请人提供）：疼痛领域一直需要开发更好的评估动物疼痛的方法，特别是与触觉或热超敏反应相反的“自发”或持续疼痛的测定。特别是头痛领域多年来遭受了没有行为分析的严重限制。目前的证据支持这样的观点：偏头痛和其他头痛是由终止于脑膜的感觉神经激活引起的。因此，这些脑膜神经末梢的实验诱导激活已被用于研究头痛机制。一项重大突破是证明化学脑膜（硬脑膜）刺激诱导清醒大鼠的面部异常性疼痛，首次提供了动物头痛的行为模型。我们现在建议追求我们认为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增加。这可以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，其已被用作评估自发性疼痛的方法。硬脑膜刺激还诱导了同侧面部“梳理”或摩擦的短暂初始期，这主要是用后爪而不是前爪完成的。关键的是，这些行为变化部分被曲普坦预处理阻断。我们现在建议通过在大鼠中更详细地描述该模型来追求这些发现，然后使用相同的方法在小鼠中建立该模型。大鼠实验将：1）评估该模型的剂量-反应曲线，以找到足以产生稳健的行为反应的应用的炎性介质的最低浓度，2）测量持续应用的药剂的CSF水平以研究通过硬脑膜的扩散量，和3）追求EEG谱的变化的初步发现，包括θ活动的增加，在接受硬脑膜刺激的大鼠中，这与安静觉醒的“休息”增加有关。对小鼠的研究将比较不同品系的伤害性反应和曲坦敏感性，并确定高反应品系与低反应品系的顺序是否与先前在其他疼痛模型中发现的顺序不同。这将为未来的研究开辟一条途径，以确定对硬脑膜刺激和曲坦敏感性反应的遗传决定因素。除了具有与刺激诱发的超敏反应相反的“自发”疼痛的潜在相关性的意义之外，该模型还具有避免应用特别困难的von Frey测试的必要性的优点 鼠标中。将进行补充研究，以检查神经激活的解剖标志物（fos和pERK），以将浅表或深背角板层以及其他中心区域的激活与行为反应的幅度相关联。