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的方法来评估动物的疼痛，特别是测定 与触觉或热敏感性相反的“自发”或持续性疼痛。头痛领域在 特别是多年来受到没有行为测定的严重限制。目前的证据 现在支持偏头痛和其他头痛是由感觉神经的激活引起的观点， 在脑膜中结束。因此，实验诱导的这些脑膜神经末梢的激活具有 被用来研究头痛的机制。一个重大突破是证明了化学物质 脑膜（硬脑膜）刺激诱导清醒大鼠的面部异常性疼痛，首次提供了一种行为学上的 动物头痛模型。我们现在建议寻求我们认为是进一步突破的东西， 头痛研究：化学刺激后“自发”行为变化的新观察 大鼠的硬脑膜。核心发现是对正常探索行为的抑制，以及伴随的 “休息”行为或安静清醒的数量增加。这可以被认为是一个例子， 抑制先天行为/运动活动的更普遍的现象，其已被用作 评估自发性疼痛的方法。硬脑膜刺激也引起了同侧短暂的初始期 主要用后爪而不是前爪进行的面部“梳理”或摩擦。关键是，这些 行为改变被曲普坦预处理部分阻断。我们现建议跟进这些调查结果 通过在大鼠中更详细地描述该模型，然后使用相同的方法也建立该模型， 小鼠模型。在大鼠中的实验将：1）评估该模型的剂量-反应曲线，以发现 所应用的炎症介质的最低浓度足以产生稳健的行为 反应，2）测量持续应用的药剂的CSF水平以研究通过药物的扩散量。 硬脑膜，3）寻求EEG频谱变化的初步发现，包括θ增加 在接受硬脑膜的大鼠中， 刺激。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，并确定高与低反应菌株的顺序是否与发现的不同 以前的疼痛模型。这将为未来的研究开辟一条途径， 硬脑膜刺激反应和曲坦敏感性的决定因素。除了拥有一个 与刺激诱发的超敏反应相反，“自发性”疼痛的潜在相关性，该模型还具有 它的优点是避免了应用冯弗雷测试的必要性，这在 老鼠.将进行补充研究，以检查神经激活的解剖标记（fos和 pERK）与浅表或深背角板层以及其他中心区域的激活相关， 行为反应的强度。