Opioid Analgesia in Awake Mice

描述（由申请人提供）：在首次被人类使用后很长时间，麻醉剂仍然是临床疼痛最广泛使用和有效的治疗方法，尽管它们有缺点：许多副作用，耐受性的发展和药物滥用的机会。需要遗传和分子生物学技术在解决与麻醉剂相关的问题方面取得重大进展，但疼痛调节几乎只在大鼠中进行了研究。该提案的目标是开发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，延髓中缝大肌（RM）细胞的放电预测了全身吗啡给药前后伤害性刺激引起的运动退缩的幅度和速度。与此相反，我们在麻醉小鼠的初步结果表明，RM细胞放电预测稳态调整，但不撤出伤害性刺激，无论是之前或之后吗啡。该提案的第一个目的是确定麻醉小鼠RM细胞调节的潜在靶点。RM细胞对清醒动物中阿片类镇痛的贡献（如果有的话）尚未确定。这个建议的第二个目的是测试小鼠RM细胞是否介导清醒小鼠的吗啡镇痛，即使我们的初步结果表明，它们在麻醉小鼠中不这样做。在大鼠中，RM神经元保护重要的稳态功能，如睡眠和进食，免受干扰。为了测试这种鼠RM细胞是否类似地捍卫稳态，将记录RM神经元的活性，同时未麻醉的小鼠自然地循环通过睡眠和觉醒状态并喝水。阿片类药物在遗传学上易于处理的小鼠中作用的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.