Mechanistic studies of opioid-induced exacerbation of chronic pain responses

由感觉神经纤维探测到的疼痛(有害)刺激警告我们潜在的和实际的组织损伤。痛感是我们生存的基础，但有时我们需要超越这种保护系统来逃离危险的情况。为了实现这一点，一类抑制性分子(阿片类药物)充当了天然的内部止痛药。这些化学信使在大脑和脊髓中与疼痛相关的区域产生，并作用于神经细胞上特定的蛋白质受体来减轻疼痛。阿片类药物，如吗啡，作用于这些相同的受体，经常被开出治疗疼痛的处方。像许多脊髓和大脑一样，疼痛通路和阿片受体系统并不是硬连线的，暴露在痛苦的刺激或药物中可以改变这些通路的运作方式，并从长远来看改变疼痛的体验。对啮齿动物的临床和实验研究都表明，在痛觉回路被激活之前使用阿片类药物，如吗啡，实际上会恶化后来的疼痛体验。虽然这似乎只是理论上的兴趣，但许多人长时间服用阿片类药物，特别是女性。了解阿片类药物治疗如何改变中枢神经系统对随后疼痛输入的处理将创造有价值的新知识，这将对终身健康产生影响。这一点尤其重要，因为骨关节炎等以疼痛为主要症状的疾病的发病率随着年龄的增长而增加，并对日常活动产生负面影响。使用众所周知的慢性疼痛啮齿动物模型，我们将研究之前和持续的吗啡治疗如何改变身体对疼痛伤害的反应方式，重点放在关键的疼痛处理区域-包括脊髓。我们将使用一种新的实验方法来同时记录脊髓上的神经元群体的活动，以了解先前的阿片类药物治疗如何影响疼痛输入的处理。我们还将利用这些信息制作一张改变后的脊髓活动的地图，为后续的解剖学研究确定重点区域。然后，我们将使用尖端显微镜方法来研究这些脊髓痛觉回路，提供证据表明之前的阿片类药物治疗是否加强了来自身体的痛感神经纤维与接受其输入的脊髓神经元之间的连接。这些连接的加强将体验到更大的痛感，这种新的显微镜方法可以比其他技术更快地测量大量已识别的连接。由于阿片受体的持续激活已知会降低其抑制功能，我们也将使用这种显微镜方法来量化感觉纤维终末内受体的数量和位置的变化。我们将测量体内自然存在的阿片分子，以确定水平的变化是否也有助于这些影响。最后的实验将探索一种名为BDNF的分子在吗啡的这些效应中的作用。众所周知，BDNF在改变大脑和脊髓的兴奋性方面发挥着重要作用，我们将在慢性疼痛模型中确定选择性地移除脊髓中的这一分子是否逆转了吗啡诱导的疼痛行为易化。这些实验将结束我们对吗啡促进疼痛反应过程的理解，并将为未来逆转这些事件提供一个目标。更多地了解阿片类药物如何改变身体对未来疼痛伤害的反应，对于支持以处方行为为重点的政策变化非常重要。此外，这一知识还将为旨在逆转阿片类药物引起的疼痛回路变化的方法提供新的想法，减少生活在先前阿片类药物治疗后果中的人数。

Painful (noxious) stimuli, detected by sensory nerve fibres, warn us of potential and actual tissue damage. The sensation of pain is fundamental to our survival, but sometimes we need to override this protective system to escape a dangerous situation. To make this possible, an inhibitory class of molecules (opioids) act as natural internal painkillers. These chemical messengers are produced in pain-related regions of the brain and spinal cord, and act at specific protein receptors on neuronal cells to reduce pain. Opioid drugs, such as morphine, act at these same receptors and are often prescribed to treat pain. Like much of the spinal cord and brain, the pain pathways and the opioid receptor system are not 'hard-wired', and exposure to painful stimuli or drugs can change the way these pathways function and alter the experience of pain in the longer term.Both clinical and experimental studies in rodents show that use of opioid drugs, like morphine, before pain circuits are activated actually worsens the experience of pain later. Although this may appear of theoretical interest only, many people are prescribed opioids for long durations, especially females. Understanding how opioid treatment changes the processing of subsequent painful inputs by the central nervous system will create valuable new knowledge, which will impact upon life-long health. This is especially important as the incidence of diseases that have pain as the major symptom, like osteoarthritis, increases with age and negatively influences everyday activities.Using well-understood rodent models of chronic pain, we will investigate how prior and continued morphine treatment changes the way the body responds to a painful injury, focusing on key pain processing areas - including the spinal cord. We will use a novel experimental approach to simultaneously record activity from populations of neurones across the spinal cord to understand how prior opioid treatment affects the processing of painful inputs. We will also use this information to produce a map of altered spinal cord activity, identifying regions to focus on for subsequent anatomical investigations. We will then use a cutting-edge microscopy approach to study these spinal pain circuits, providing evidence of whether prior opioid treatment strengthens connections between pain-sensing nerve fibres from the body and the spinal neurones that receive their input. A strengthening of these connections would be experienced as greater pain sensation, and this new microscopy approach allows measurement of a large number of identified connections much faster than other techniques. As continued activation of the opioid receptors is known to reduce their inhibitory function, we will also use this microscopy method to quantify changes in the number and location of receptors within sensory fibre terminals. We will measure opioid molecules naturally present in the body to identify whether changes in levels also contribute to these effects. The final experiments will probe the contribution of a molecule called BDNF in these effects of morphine. BDNF is known to play important roles in altering the excitability of the brain and spinal cord, and we will establish whether selectively removing this molecule in the spinal cord reverses morphine-induced facilitation of pain behaviour in a model of chronic pain. These experiments will close the loop in our understanding of the processes by which morphine can facilitate painful responses, and will provide a target for reversing these events in the future. Greater knowledge of how opioid drugs alter the response of the body to future painful injuries is important to support changes in policy focused upon prescribing behaviour. Furthermore, this knowledge will also provide new ideas for approaches aimed at reversing opioid drug-induced changes in pain circuitry, reducing the number of people living with the consequences of prior opioid treatment.