Opioid Analgesia in Awake Mice

描述（由申请人提供）：在人类首次使用麻醉品很久之后，麻醉品仍然是临床疼痛的最广泛和最有效的治疗方法，尽管它们有许多缺点：副作用多，耐受性的发展，以及滥用药物的机会。遗传和分子生物学技术需要在解决与麻醉品有关的问题上取得重大进展，但疼痛调节几乎只在大鼠身上进行了研究。这项提议的目标是发展小鼠作为研究吗啡镇痛及其副作用的模型，从而允许现代分子和遗传方法影响疼痛管理。在麻醉大鼠中，中缝大髓细胞的放电预测了全身吗啡前后对有害刺激的运动退出的大小和速度。相比之下，我们在麻醉小鼠身上的初步结果表明，无论是在吗啡之前还是之后，RM细胞放电都预示着体内平衡的调整，而不是有害刺激的退出。本建议的第一个目的是确定麻醉小鼠RM细胞调节的潜在靶点。在清醒的动物中，RM细胞对阿片类镇痛的贡献，如果有的话，还没有被定义。本提案的第二个目的是测试小鼠RM细胞是否在清醒小鼠中介导吗啡镇痛，即使正如我们的初步结果所表明的那样，它们在麻醉小鼠中不这样做。在大鼠中，RM神经元保护重要的体内平衡功能，如睡眠和进食，不受干扰。为了测试这种小鼠RM细胞是否同样捍卫稳态，在未麻醉的小鼠自然地在睡眠和清醒状态之间循环并喝水时，将记录RM神经元的活动。阿片类药物在遗传易感小鼠中的作用机制模型将允许开发最小化副作用和最大化镇痛的治疗策略。

DESCRIPTION (provided by applicant): Long after their first use by humans, narcotics remain the most widely used and effective treatment for clinical pain despite their disadvantages: numerous side effects, the development of tolerance, and the opportunity for drug abuse. Genetic and molecular biological techniques are needed to make major advances in addressing the problems associated with narcotics but pain modulation has been almost exclusively studied in the rat. The goal of this proposal is to develop the mouse as a model for studying morphine analgesia and its side effects and thereby allow modern molecular and genetic methods to impact pain management. In the anesthetized rat, the discharge of cells in the medullary raphe magnus (RM) predicts the magnitude and speed of motor withdrawals from noxious stimulation both before and after systemic morphine. In contrast, our preliminary results in anesthetized mouse suggest that RM cell discharge predicts homeostatic adjustments but not withdrawals from noxious stimulation, either before or after morphine. The first aim of this proposal is to identify potential targets of RM cell modulation in the anesthetized mouse. The contribution of RM cells to opioid analgesia in awake animals, if any, has not been defined. The second aim of this proposal is to test whether murine RM cells mediate morphine analgesia in the awake mouse, even if, as our preliminary results suggest, they do not do so in the anesthetized mouse. In the rat, RM neurons protect important homeostatic functions, such as sleep and feeding, from interruption. To test whether this murine RM cells similarly defend homeostasis, the activity of RM neurons will be recorded while unanesthetized mice naturally cycle through sleep and wake states and drink water. A mechanistic model for opioid action in the genetically tractable mouse will allow development of therapeutic strategies that minimize side effects and maximize analgesia.