Opioid Analgesia in Awake Mice

描述（由申请人提供）：麻醉剂在首次被人类使用很久之后，仍然是临床疼痛最广泛使用和最有效的治疗方法，尽管它们有许多缺点：副作用较多、产生耐受性以及药物滥用的机会。需要遗传和分子生​​物学技术才能在解决与麻醉品相关的问题方面取得重大进展，但疼痛调节几乎完全是在大鼠身上进行的研究。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，从而使现代分子和遗传方法能够影响疼痛管理。在麻醉大鼠中，中缝大肌 (RM) 中细胞的放电可预测全身吗啡前后从有害刺激中退出运动的幅度和速度。相比之下，我们在麻醉小鼠中的初步结果表明，无论是在吗啡之前还是之后，RM 细胞放电可以预测稳态调整，但不能预测从有害刺激中的退出。该提案的首要目的是确定麻醉小鼠 RM 细胞调节的潜在靶点。 RM 细胞对清醒动物阿片类镇痛的贡献（如果有的话）尚未确定。该提案的第二个目的是测试鼠 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表明的那样，它们在麻醉小鼠中不会介导吗啡镇痛。在大鼠中，RM 神经元可保护重要的稳态功能，例如睡眠和进食，使其免受干扰。为了测试这种小鼠 RM 细胞是否同样能保护体内平衡，在未麻醉的小鼠自然循环睡眠和清醒状态并喝水时，将记录 RM 神经元的活动。在遗传易驯化的小鼠中阿片类药物作用的机制模型将允许开发最大限度地减少副作用和最大限度地镇痛的治疗策略。

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.