Medullary Circuitry of Pain Facilitation

描述(由申请人提供：对疼痛和止痛感兴趣的研究人员的注意力已经越来越多地从急性疼痛机制转向导致持续疼痛状态的过程。现在有明确的功能证据表明，脑干调节系统有助于与神经损伤和炎症相关的持续性疼痛。在中脑导水管周围灰质和延髓头端腹内侧(RVM)，最具特性的调节系统具有重要的联系，在不同的条件下被用来增强或抑制伤害感受。本提案的重点是RVM。在过去的十年里，我的实验室已经证明，来自RVM的疼痛抑制和促进疼痛的影响是由两种类型的神经元介导的，“上细胞”和“外细胞”，它们对伤害感受施加净促进影响，而“离细胞”具有净抑制作用。这项建议的首要目标是了解这些神经元的属性和关系中的活动依赖变化如何导致神经损伤后的异常疼痛，以及在慢性炎症期间。利用单细胞记录和行为药理学相结合的方法，拟议的实验将测试神经损伤动物上、外细胞机械阈值的变化是否对行为超敏反应重要，将慢性炎症期间RVM神经元的变化与神经损伤后看到的变化进行对比，并确定两种模型中上细胞激活的驱动因素。如果我们要为患者开发更好的治疗方法，更好地理解慢性疼痛背后的分子、细胞和电路水平的机制是必不可少的。现在有越来越多的证据表明，病理性疼痛状态至少在一定程度上是由大脑本身的变化驱动的。已知下行调节通路介导自上而下的伤害性处理的调节，将皮质和边缘的影响传递到背角。这些途径也通过正反馈和负反馈环路与提升传递紧密地交织在一起。因此，未能包括下行调节通路的持续性疼痛模型必然是不完整的。通过研究已知的伤害性调制神经元的特性在从急性疼痛到慢性疼痛的转变过程中是如何变化的，本研究填补了我们知识的一个重要空白。 与公共健康相关：我们现在明白，大脑主动控制我们对痛苦输入的敏感度。因此，大脑调节系统的失衡，从而有利于疼痛的传递，在慢性疼痛状态下可能是重要的。这项申请中提出的工作将研究脑干中疼痛调制神经元的特性，以确定它们是如何改变以支持慢性疼痛的。

DESCRIPTION (provided by applicant: The attention of investigators interested in pain and analgesia has been increasingly directed beyond acute pain mechanisms towards processes that give rise to persistent pain states. There is now clear functional evidence that brainstem modulatory systems contribute to persistent pain associated with nerve injury and inflammation. The best characterized modulatory system has important links in the midbrain periaqueductal gray and rostral ventromedial medulla (RVM), and is recruited to enhance or inhibit nociception under different conditions. The present proposal focuses on the RVM. Over the last ten years, my laboratory has demonstrated that pain-inhibiting and pain- facilitating influences from the RVM are mediated by two classes of neurons, "ON-cells," which exert a net facilitating influence on nociception, and "OFF-cells," which have a net inhibitory action. The overarching goal of this proposal is to understand how activity- dependent changes in the properties and relationships of these neurons contribute to abnormal pain following nerve injury, and during chronic inflammation. Using a combination of single-cell recording and behavioral pharmacology, the proposed experiments will test whether changes in the mechanical thresholds of ON- and OFF-cells in nerve-injured animals are important for behavioral hypersensitivity, contrast changes in RVM neurons during chronic inflammation with those seen following nerve injury, and identify drivers of ON-cell activation in both models. A better understanding of molecular, cellular, and circuit-level mechanisms underlying chronic pain is essential if we are to develop better treatments for patients. There is now increasing evidence that pathological pain states are at least in part driven by changes in the brain itself. Descending modulatory pathways are known to mediate top-down regulation of nociceptive processing, transmitting cortical and limbic influences to the dorsal horn. These pathways are also intimately intertwined with ascending transmission through positive and negative feedback loops. Models of persistent pain that fail to include descending modulatory pathways are thus necessarily incomplete. By examining how the properties of known nociceptive modulatory neurons are transformed during the transition from acute to chronic pain, the present studies fill an important gap in our knowledge. PUBLIC HEALTH RELEVANCE: We now understand that the brain actively controls our sensitivity to painful inputs. An imbalance in the brain's modulatory systems so that pain transmission is favored can therefore be important in chronic pain states. The work proposed in this application will study the properties of pain-modulating neurons in the brainstem to determine how they are altered to support chronic pain.