Medullary Circuitry of Pain Facilitation

描述（由申请人提供）：对疼痛和镇痛感兴趣的研究者的注意力已经越来越多地从急性疼痛机制转向引起持续疼痛状态的过程。现在有明确的功能证据表明，脑干调节系统与神经损伤和炎症相关的持续疼痛有关。最具特征的调节系统在中脑导水管周围灰质和吻侧腹内侧髓质（RVM）中具有重要的联系，并在不同情况下参与增强或抑制伤害感受。目前的建议侧重于RVM。在过去的十年里，我的实验室已经证明，RVM的疼痛抑制和疼痛促进作用是由两类神经元介导的，“on细胞”对伤害感觉施加净促进作用，“off细胞”具有净抑制作用。这项提议的首要目标是了解这些神经元的性质和关系的活动依赖性变化如何导致神经损伤后和慢性炎症期间的异常疼痛。采用单细胞记录和行为药理学相结合的方法，实验将测试神经损伤动物ON-和off细胞机械阈值的变化是否对行为超敏反应有重要影响，对比慢性炎症期间RVM神经元的变化与神经损伤后的变化，并确定两种模型中ON-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，更好地了解慢性疼痛的分子、细胞和回路水平机制是必不可少的。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自身的变化所驱动的。已知下行调节通路介导自上而下的伤害性加工调节，将皮层和边缘的影响传递到背角。这些路径也通过积极和消极的反馈循环与提升传播紧密地交织在一起。不包括下行调节通路的持续疼痛模型必然是不完整的。通过研究在从急性疼痛到慢性疼痛的转变过程中，已知的伤害性调节神经元的特性是如何转变的，目前的研究填补了我们知识上的一个重要空白。

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.