Contributions of prefrontal-midbrain-spinal cord network dynamics to the development and maintenance of chronic neuropathic pain.

长期疼痛（慢性疼痛）广泛流行，严重影响患者的健康，并给我们的经济带来巨大的成本。为急性（正常）疼痛开发的止痛药物对大多数慢性疼痛患者无效。因此，慢性疼痛仍然是最大的未满足的临床需求之一。组织损伤由外周神经检测，外周神经将疼痛信息传递到脊髓（SC），在脊髓中发生初始疼痛处理。然后，疼痛信息传递到大脑，在一个分布式的大脑区域网络中进行进一步处理，这些区域产生疼痛体验的感觉和情感方面。我们对疼痛的理解的最新进展表明，改变大脑中的疼痛处理，而不是在周围神经系统中，可能形成慢性疼痛障碍的关键部位，因此，如果我们要为患者开发更有效的治疗方法，就需要更好地了解这些过程。疼痛体验不是固定的，并且可以通过影响脊髓疼痛处理的下行疼痛调节系统（DPMS）来改变，这反过来又调节疼痛信息流向大脑。因此，疼痛体验是由脊髓疼痛处理的下行控制、由此产生的上行疼痛信息和大脑中的疼痛处理之间的相互作用决定的。在慢性疼痛中，外周疼痛输入的幅度与疼痛体验之间的关系丧失，使得疼痛维持超过组织损伤的时期。我们假设，在这种情况下，中枢神经系统网络的变化，疼痛信息的处理改变了DPMS控制脊柱疼痛处理，这样做，有助于增强疼痛感知和负面情绪。具体来说，最近的研究结果特别重视内侧前额叶皮层（mPFC），这是一个参与高级处理的大脑区域，例如情绪的产生和调节，以及情绪与感官信息的整合，然后进入意识意识。然而，理解的mPFC在疼痛中的作用的基础机制还没有完全理解，有很少的信息与其他大脑区域的相互作用，介导的疼痛感觉和/或情绪。这些问题正是我们所提出的调查要解决的问题。mPFC和中脑导水管周围灰质（PAG）之间存在直接联系;后者是DPMS的关键协调者。我们认为，mPFC-PAG连接是重要的途径，介导的影响，高阶PFC功能的低阶疼痛处理在脊髓中，从而有助于改变慢性疼痛的疼痛感觉和情绪。在建立的慢性疼痛动物模型中，我们将在慢性疼痛的发展过程中操纵和抑制麻醉和行为动物中mPFC-PAG-SC网络内的通信。这将使我们能够将潜在的机制与疾病生物学联系起来。重要的是，在多个时间点选择性失活mPFC-PAG连接将能够识别它们对疼痛状态的感觉和情感方面的动态贡献。这项研究将产生新的数据，说明大脑中高阶疼痛处理的改变之间的因果关系，它与DPMS的相互作用以及疼痛感觉和负面情绪的增强体验。这些发现将进一步加深我们对导致慢性疼痛的大脑机制的理解，并将为人类患者的研究提供支持和信息。长期的益处包括确定有效治疗策略的潜在靶点。

Long term pain (chronic pain) is widely prevalent, severely impacts upon a patient's health and poses an enormous cost to our economy. Pain relieving drugs developed for acute (normal) pain are ineffective in the majority of chronic pain patients. As a result, chronic pain remains one of the greatest unmet clinical needs. Tissue damage is detected by peripheral nerves that convey pain information to the spinal cord (SC) where initial pain processing occurs. Pain information then travels to the brain for further processing in a distributed network of brain regions that produce sensory and emotional aspects of the pain experience. Recent advances in our understanding of pain indicate that alterations to pain processing in the brain, rather than in the peripheral nervous system, may form a critical locus for chronic pain disorders and, as such, a better understanding of these processes is required if we are to develop more effective treatments for patients. The pain experience is not fixed, and can be altered by a descending pain modulatory system (DPMS) that affects spinal pain processing, which in turn modulates the flow of pain information to the brain. Thus the pain experience is determined by the interplay between descending control of spinal pain processing, the resultant ascending pain information, and pain processing in the brain. In chronic pain the relationship between the magnitude of peripheral pain input and the pain experience is lost, such that pain is maintained beyond the period of tissue damage. We postulate that, in these circumstances, changes in central nervous system networks that process pain information alter the DPMS control of spinal pain processing and, in so doing, contribute to enhanced pain perception and negative emotion. Specifically, recent findings have placed particular importance on the medial prefrontal cortex (mPFC), an area of the brain involved in higher processing such as the generation and regulation of emotion, and the integration of emotional with sensory information that then feeds into conscious awareness. However, understanding of the mechanisms that underlie the role of the mPFC in pain are not fully understood and there is little information about its interactions with other brain regions that mediate effects on pain sensation and/or emotion. It is these questions our proposed investigations will address. Direct connections exist between the mPFC and the midbrain periaqueductal grey (PAG); the latter being a key orchestrator of the DPMS. We propose that mPFC-PAG connections are important pathways that mediate effects of high order PFC function on lower order pain processing in the spinal cord, and thus contribute to altered pain sensation and emotion in chronic pain. In an established animal model of chronic pain we will manipulate, and characterise, the communication within the mPFC-PAG-SC network in anaesthetised and behaving animals during the development of chronic pain. This will enable us to relate underlying mechanisms to disease symptomology. Critically, selective inactivation of mPFC-PAG connections at a number of time points will enable identification of their dynamic contributions to sensory and emotional aspects of the pain state as it progresses. The study will generate novel data about the causal relationship between alterations to high-order pain processing in the brain, its interplay with the DPMS and the enhanced experience of pain sensation and negative emotion. The findings will further our understanding of brain mechanisms that contribute to chronic pain and will support and inform studies in human patients. The long-term benefits include the identification of potential targets for effective therapeutic strategies.