Rodent Behavioral Model of Ongoing Headache Pain

持续头痛的啮齿动物行为模型

• 批准号: 8621685
• 负责人: Andrew Mark Strassman
• 金额: $ 26.1万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621685
• 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

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.

项目摘要 疼痛领域一直需要开发更好地评估动物疼痛的方法，尤其是测定法 与触觉或超敏反应相反的“自发”或持续的疼痛。头痛领域 多年来，特别是没有行为分析的严重局限性。当前的证据 现在支持这样一个想法，即偏头痛和其他头痛是由于感官神经的激活而引起的 结束脑膜。因此，这些脑膜神经末端的实验诱导的激活具有 用于研究头痛机制。一个重大突破是证明化学的证明 脑膜（硬脑膜）刺激引起的醒着大鼠的面部异常性ni症，这是行为首次提供的 动物头痛的模型。我们现在建议追求我们认为的进一步突破 头痛研究：化学刺激后“自发”行为的变化的新观察 大鼠的硬脑膜。核心发现是对正常探索行为的抑制作用，并且是伴随的 增加“休息”行为或安静清醒的数量。这可能被认为是一个例子 抑制先天行为/运动活性的更一般现象，已被用作 评估自发疼痛的方法。硬脑膜刺激还引起了同侧的短期初期 面部“修饰”或摩擦主要是用后爪而不是前爪进行的。批判性，这些 行为变化通过曲坦预处理部分阻止。我们现在建议追求这些发现 通过在大鼠中更详细地表征此模型，然后使用相同的方法也建立了这一点 小鼠模型。大鼠中的实验将：1）评估该模型的剂量响应曲线，以便找到 最低的施加炎症介质足以产生可靠的行为 响应，2）测量持久施用药物的CSF水平，以研究通过 硬脑膜和3）追求脑电图变化的初步发现，包括theta的增加 活动与安静清醒的“休息”增加相关，在接受硬脑膜的大鼠中 刺激。在小鼠中的研究将比较其伤害性反应和triptan的不同菌株 敏感性，并确定高与低响应菌株的顺序是否不同于发现的 以前用于其他疼痛模型。这将为识别遗传的未来研究开辟一条途径 对硬脑膜刺激和曲普坦灵敏度的反应的决定因素。除了拥有一个 与刺激引起的超敏反应相反的“自发”疼痛的潜在相关性，该模型也具有 它避免进行冯·弗雷测试的必要性的优势，这在 老鼠。将进行互补研究以检查神经激活的解剖标记（FOS和FOS和 PERK）与表面或深层角板层以及其他中央区域中的激活相关 行为反应的大小。