Mechanistic studies of opioid-induced exacerbation of chronic pain responses

感觉神经纤维检测到的疼痛（有害）刺激警告我们潜在的和实际的组织损伤。疼痛的感觉是我们生存的基础，但有时我们需要超越这种保护系统来逃避危险的情况。为了使这成为可能，抑制类分子（阿片类药物）作为天然的内部止痛药。这些化学信使产生于大脑和脊髓的疼痛相关区域，并作用于神经元细胞上的特定蛋白质受体以减轻疼痛。阿片类药物，如吗啡，作用于这些相同的受体，通常用于治疗疼痛。与脊髓和大脑的大部分部位一样，疼痛通路和阿片受体系统并不是“硬连线”的，暴露于疼痛刺激或药物可以改变这些通路的功能方式，并改变长期的疼痛体验。啮齿动物的临床和实验研究都表明，在疼痛回路被激活之前使用阿片类药物，如吗啡，实际上会减少以后的疼痛体验。虽然这可能只是理论上的兴趣，但许多人长期服用阿片类药物，尤其是女性。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，这将影响终身健康。这一点尤其重要，因为以疼痛为主要症状的疾病（如骨关节炎）的发病率会随着年龄的增长而增加，并对日常活动产生负面影响。我们将使用众所周知的慢性疼痛啮齿动物模型，研究先前和持续的吗啡治疗如何改变身体对疼痛损伤的反应，重点关注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整个脊髓神经元群体的活动，以了解先前的阿片类药物治疗如何影响疼痛输入的处理。我们还将使用这些信息来制作脊髓活动改变的地图，确定后续解剖学研究的重点区域。然后，我们将使用尖端的显微镜方法来研究这些脊髓疼痛回路，提供证据证明先前的阿片类药物治疗是否加强了身体疼痛感测神经纤维与接受其输入的脊髓神经元之间的连接。这些连接的加强将被体验为更大的疼痛感，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。由于已知阿片受体的持续激活会降低其抑制功能，因此我们还将使用这种显微镜方法来量化感觉纤维末端内受体数量和位置的变化。我们将测量体内天然存在的阿片类分子，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作用中的作用。已知BDNF在改变大脑和脊髓的兴奋性方面起重要作用，我们将确定在慢性疼痛模型中选择性地去除脊髓中的这种分子是否逆转吗啡诱导的疼痛行为的促进。这些实验将结束我们对吗啡促进疼痛反应的过程的理解，并将为未来逆转这些事件提供目标。更多地了解阿片类药物如何改变身体对未来疼痛损伤的反应，对于支持专注于处方行为的政策变化非常重要。此外，这些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思路，减少因既往阿片类药物治疗而生活的人数。

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.