Medullary Circuitry of Pain Facilitation

疼痛促进的髓质回路

• 批准号: 8065848
• 负责人: Mary Magdalen Heinricher
• 金额: $ 32.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065848
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Animals; Attention; Behavioral; Brain; Brain Stem; Cells; Chronic; Cutaneous; Data; Down-Regulation; Exhibits; Feedback; Goals; Hypersensitivity; Indium; Inflammation; Injury; Knowledge; Laboratories; Ligation; Link; Mechanics; Mediating; Midbrain structure; Modeling; Molecular; Muscimol; Nerve; Neurons; Nociception; Pain; Pathway interactions; Patients; Persistent pain; Play; Population; Process; Property; Protocols documentation; Recruitment Activity; Research; Research Personnel; Role; Spinal nerve structure; System; Testing; Work; allodynia; behavioral pharmacology; chronic pain; dorsal horn; inflammatory neuropathic pain; injured; interest; mechanical allodynia; midbrain central gray substance; nerve injury; neural circuit; neuropeptide Y; novel; pain inhibition; painful neuropathy; public health relevance; research study; response; transmission process

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.

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越来越多地从急性疼痛机制转向引起持续性疼痛状态的过程。现在有明确的功能证据表明，脑干调节系统导致与神经相关的持续性疼痛最具特征的调节系统在中脑导水管周围灰质和头端腹内侧延髓（RVM）中具有重要的联系，并被招募来增强或抑制不同情况下的伤害感受。在过去的十年里，我的实验室已经证明，RVM 的疼痛抑制和促进疼痛作用是由两类神经元“ON 细胞”介导的，它们发挥着网络作用。促进对伤害感受的影响，以及具有净抑制作用的“OFF细胞”。该提案的首要目标是了解这些神经元的特性和关系的活动依赖性变化如何导致神经损伤后的异常疼痛，以及慢性炎症期间。 结合单细胞记录和行为药理学，拟议的实验将测试神经损伤动物中 ON 和 OFF 细胞机械阈值的变化是否对行为超敏反应重要，对比慢性炎症期间 RVM 神经元的变化神经损伤后观察到的结果，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背后的分子、细胞和回路机制至关重要。现在越来越多的证据表明，病理性疼痛状态至少部分是由大脑本身的变化驱动的。已知下降调节途径介导伤害感受处理的自上而下的调节，将皮质和边缘影响传递到背角。这些途径还通过正反馈环和负反馈环与上行传播紧密地交织在一起。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节神经元的特性在从急性疼痛到慢性疼痛的转变过程中如何转变，本研究填补了我们知识中的一个重要空白。 公共健康相关性：我们现在了解到，大脑主动控制我们对疼痛输入的敏感性。因此，大脑调节系统的不平衡有利于疼痛的传递，这对于慢性疼痛状态非常重要。本申请中提出的工作将研究脑干中疼痛调节神经元的特性，以确定如何改变它们以支持慢性疼痛。