Identifying more clinically effective analgesic regimens and potential strain differences in pain perception in mice using a novel Operant Pain Assay

该项目旨在改善在科学研究中经历潜在疼痛程序的实验室小鼠的疼痛缓解。我们估计，每年约有13%（约400 k英国，全球> 400万）的小鼠用于研究，将经历潜在的疼痛程序，有效的疼痛缓解可以减少或预防疼痛。不幸的是，许多目前给予小鼠的疼痛缓解药物似乎部分或完全无效。这对动物福利和从这些小鼠收集的科学数据的价值都是一个重大挑战。为了改善小鼠的疼痛缓解，我们需要：-一种更好的方法来测试疼痛缓解药物在治疗程序相关疼痛方面的有效性。- 确定新的止痛药是否比目前使用的更好。- 确定在小鼠品系之间观察到的镇痛药物有效性差异是否与潜在疼痛体验的差异有关。为了回答这些基本问题，我们有两个相互关联的目标。目的1：研究常用和新型镇痛药物对三种常见实验小鼠的镇痛效果。这将分3个阶段完成，这将确保使用最少数量的小鼠，并且这些小鼠暴露于可能达到目标的最轻微疼痛。第一阶段将使用一种新的自动化方法（口面操作性疼痛测定）快速评估目前使用的和新的止痛药在最常见的小鼠品系中的有效性。这被认为比目前使用的方法更好，因为它只产生轻微和短暂的疼痛刺激，小鼠能够关闭，并且是实际程序后经历的疼痛的更好模型。第二阶段将测试第一阶段确定的三种最有效的药物在另外两种常见小鼠品系中的有效性。第3阶段将测试三种最有效的止痛形式（来自第1阶段和第2阶段）在治疗相同常见小鼠品系的术后疼痛中的有效性。作为繁殖计划的一部分，这些小鼠将接受常规输精管切除术，并将使用一系列经验证的小鼠疼痛措施来测试止痛药物的有效性，包括：自发行为（例如行走和直立）、疼痛相关行为（例如抽搐和扭动）的存在、疼痛相关面部表情以及筑巢和挖洞的意愿和能力（先天小鼠行为）。药物的有效性将通过确定哪些药物可以恢复和维持正常的行为模式并减少疼痛相关行为的表达来确定。目标2将确定本项目中使用的常见小鼠品系之间所经历的疼痛是否存在潜在差异。使用第1和第2阶段的口面操作性疼痛测定数据，我们可以研究这些小鼠的疼痛体验，因为它要求每只小鼠平衡它们寻求可口奖励的动机和它们感知到的轻微疼痛。如此复杂的任务无法通过简单的反射反应来完成，因为这些反射反应不依赖于动物有意识地体验疼痛。使用来自第3阶段的手术后数据使我们能够确定手术后疼痛相关行为表达的应变差异是否与在第1阶段和第2阶段观察到的奖励寻求的应变差异相关。这使我们能够确定这些差异是否与菌株之间疼痛体验的差异有关。该项目将确定哪些止痛药物最有效，对于特定类型（菌株）在常规使用的外科手术后，允许提出建议并实施，以改善用于科学研究的小鼠的福利和对这些小鼠进行的科学质量。动物

This project aims to improve the pain relief administered to laboratory mice that undergo potentially painful procedures in scientific research. We estimate that annually ~13% (~400k UK, >4 million worldwide) of mice used in research, will undergo potentially painful procedures where effective pain relief could reduce or prevent the pain experienced. Unfortunately, many of the current pain relieving drugs administered to mice appear to be partially or completely ineffective. This represents a major challenge for both animal welfare and the value of the scientific data collected from these mice. To achieve improved pain relief for mice we need:- A better means of testing pain-relieving drugs for their effectiveness in treating procedure-related pain. - To determine whether new pain-relieving drugs are better than those currently being used. - To determine whether or not the differences in the effectiveness of pain-relieving drugs observed between mouse strains relates to differences in the underlying experience of pain. To answer these fundamental questions, we have two interlinked objectives. Objective 1 will establish the effectiveness of routinely used and new pain-relieving drugs in three common strains of laboratory mice. This will be accomplished in 3 stages, which will ensure that the minimum number of mice are used, and that those mice are exposed the mildest pain possible to achieve of the objectives. Stage 1 will rapidly assess the effectiveness of currently used and new painkillers in the most common strains of mice using a new automated method (Orofacial Operant Pain Assay). This is considered better than currently used methods as it only produces a mild and short-lived painful stimulus that the mouse is able switch off and is a better model of the pain experienced after an actual procedure. Stage 2 will test the effectiveness of the three most effective drugs identified in stage 1 in two other common strains of mice. Stage 3 will test the effectiveness of the three most effective forms of pain-relief (from stages 1 & 2) in treating post-surgical pain in the same common strains of mice. These mice will be undergoing routine vasectomy as part of a breeding programme and the effectiveness of pain-relieving drugs will be tested using a range of validated pain measures for mice, including: spontaneous behaviour (e.g. walking and rearing), presence of pain-related behaviours (e.g. twitching and writhing), pain-related facial expressions, and the willingness and ability to nest build and burrow (innate mouse behaviours). The effectiveness of the drugs will be determined by identifying which drug(s) restore and maintain normal patterns of behaviour and reduce the expression of pain-related behaviours.Objective 2 will establish whether the pain experienced potentially differs between the common mouse strains being used in this project. Using the Orofacial Operant Pain Assay data from stages 1 and 2 allows us to investigate pain experience in these mice because it asks each mouse to balance their motivation to seek palatable reward against the mild pain they perceive. Such a complex task cannot be accomplished with a simple reflex response since these are not dependent on the animal consciously experiencing the pain. Using the post-surgical data from stage 3 enables us to determine whether strain differences in the expression of pain related behaviours following surgery correlate with strain differences in reward seeking observed at stages 1 and 2. This enables us to determine if the differences are potentially related to differences in pain experience between the strains.This project will determine which pain relieving drugs are the most effective, for a specific type (strain) of mouse following a routinely used surgical procedure allowing recommendations to be made and implemented to improve the welfare of mice used in scientific research and the quality of the science carried out on these animals.