Opioid self-administration in the assessment of post-operative pain in rats

老鼠在研究新药和治疗方法的研究中起着至关重要的作用，但这通常需要在接受手术之前使它们失去意识(麻醉)。常见的外科手术是开腹手术，即切断皮肤和下层肌肉，露出腹部器官的一种手术方式。科学家有责任确保动物从麻醉中恢复后感受到很少或根本没有疼痛。然而，因为动物无法告诉我们它们的感受，所以很难衡量这有多痛苦。科学研究表明，有一些行为对于确定开腹手术对大鼠造成多大程度的疼痛特别重要，因为手术后它们会增加，但如果提供止痛药(通常在手术前注射)就可以减少。这项研究表明，不同的镇痛剂有不同的止痛能力，这取决于给老鼠服用多少药物，以及重要的(与疼痛有关的)行为是完全消失还是只部分消失。然而，一个主要的问题是，研究人员仍然不确定他们使用的治疗是否最有效，因为无论给老鼠服用什么止痛药，通常都会出现一些微妙的行为变化。因此，目前尚不清楚这些异常活动的持续存在是否意味着大鼠仍在经历疼痛，因此，给予的止痛剂的效果如何尚不清楚。要想完全了解老鼠正在经历的事情，一种方法是给它们机会告诉我们它们的感受，但由于它们无法与我们交流，这只能是间接的。如果大鼠在手术后感到疼痛，那么，如果有机会，它们应该选择服用(自我给药)止痛药来减轻疼痛。然后，他们选择自行给药的止痛剂的量可以用来估计手术造成的疼痛程度。然而，测试这一理论的一个重要步骤是确保老鼠知道获得药物将提供疼痛缓解。正因为如此，他们将首先接受训练，将鼻子伸进测试室的一个洞中，就会无痛地引发强烈止痛药(瑞芬太尼)的注射。一旦他们知道了这一点，他们应该根据他们所经历的疼痛程度来增加他们戳鼻子的次数。这项实验的一个非常有用的方面是，它还可以用来测试其他止痛药的止痛特性。根据行为学调查的结果，将为大鼠提供一种药物，该药物应能有效缓解手术引起的疼痛。其中一种叫美洛昔康，另一种叫卡洛芬。如果这两种药物中的任何一种是在手术前给予的，并且给出的剂量完全消除了疼痛，那么当大鼠从麻醉中恢复时，他们不应该选择自我给予额外的瑞芬太尼。如果发生这种情况，那么这将是非常好的证据，表明疼痛是大鼠需要瑞芬太尼的原因。另一种证实这一点的方法是表明，如果手术类型导致更多疼痛，大鼠也会摄入更多瑞芬太尼。这些大鼠将经历4种不同的手术，这些手术会导致不同程度的疼痛，但没有一种会非常痛苦。如果大鼠即使在服用美洛昔康或卡洛芬后仍继续服用更多的瑞芬太尼，那么这将意味着美洛昔康或卡洛芬的剂量不够，需要更多的剂量。测试大鼠在手术后几天内需要多少瑞芬太尼，将产生关于引起疼痛多少、持续多长时间以及未来最好预防疼痛的止痛剂剂量的最佳信息。这些信息将对其他需要进行剖腹手术和其他类型手术的研究人员有用，从而有助于改善科学研究中所有接受手术的大鼠的福利。

Rats have a vital role in research to investigate new drugs and treatments, but this often requires that they are made unconscious (anaesthetised) before undergoing surgery. A common surgical procedure is laparotomy; an incision whereby the skin and underlying muscles are cut so the organs inside the abdomen are exposed. Scientists have a duty to ensure that after the animals experience little or no pain after they recover from anaesthesia. Because the animals cannot tell us how they feel, however, it is difficult to gauge how painful this is. Scientific research has shown that there are some behaviours that are particularly important for determining how much pain laparotomy surgery causes in rats, because they increase as a result of surgery, but can be reduced if pain relieving drugs (analgesics) are provided (usually injected prior to surgery). This research has shown that different analgesics have different abilities to reduce pain, depending on how much drug the rats are given, and on whether the important (pain-related) behaviours disappear completely or only partially. One major problem, however, is that the researchers are still unsure whether the treatments they use are the most effective, because regardless of the analgesic given to the rats, some subtle behaviour changes usually remain. It is therefore unclear whether the continued presence of these abnormal activities means the rats are still experiencing pain, and so, how effective the analgesic that was given had been. One way to try to fully understand what the rats are experiencing is to give them the opportunity to tell us how they feel, but as they cannot communicate with us, this can only be done indirectly. If the rats are experiencing pain after surgery, then, if given the chance, they should choose to take (self-administer) analgesics to reduce it. The amount of analgesic they choose to self-administer could then be used as an estimate of how much pain was caused by surgery. An essential step in testing this theory, however, is to ensure that the rats know that obtaining the drugs will provide pain relief. Because of this, they will first be trained that poking their nose into a hole in a test chamber will painlessly trigger an injection of a strong pain killer (remifentanil). Once they know this, they should increase the number of times they nose-poke according to how much pain they are experiencing. A very useful aspect of this experiment is that it can also be used to test the pain-relieving properties of other analgesic drugs. The rats will be provided with one of the drugs that, according to the results of behavioural investigations, should be effective for relieving the pain caused by surgery. One such drug is called meloxicam, and another is carprofen. If either of these is given prior to surgery, and the dose given completely eliminates pain, then the rats should not choose to self-administer additional remifentanil when they recover from anaesthesia. Is this occurs, then it will be very good evidence that pain was the reason the rats needed remifentanil. Another way to confirm this is to show that the rats will also consume more remifentanil if the type of surgery causes more pain. The rats will undergo 4 different procedures that will cause different amounts of pain, but none will be highly painful. If the rats continue take more remifentanil even after they have been given meloxicam or carprofen then this will mean that the dose of meloxicam or carprofen was not sufficient, and more was needed. Testing how much remifentanil the rats need over several days following surgery will produce the best possible information on how much pain is caused, how long it lasts and what dose of analgesic is best to prevent it in future. This information would be useful to other researchers who need to conduct laparotomy and other types of surgery as part of their research, and so help to improve the welfare of all rats undergoing surgery in scientific research.