Central mechanisms of maintenance of orofacial pain after injury

损伤后维持口面部疼痛的中心机制

• 批准号: 8250370
• 负责人: RONALD DUBNER
• 金额: $ 65.93万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-04 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250370
• 关键词: Accounting; Acute; Animal Model; Area; Behavioral; Brain Stem; Complex; Data; Disease; Exhibits; Functional disorder; GABA Receptor; Goals; Human; Hyperalgesia; Hypersensitivity; Inflammation; Injury; Knowledge; Lead; Local Anesthetics; Maintenance; Masseter Muscle; Mechanics; Modeling; Molecular; Muscle; Muscle Fibers; N-Methyl-D-Aspartate Receptors; Nerve; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Nociceptors; Operative Surgical Procedures; Orofacial Pain; Pain; Pain Disorder; Peripheral; Persistent pain; Physiological; Research; Role; Secondary Hyperalgesias; Serotonin; Signal Transduction; Site; Spinal; Staging; Tendon structure; Testing; Tissues; Trigeminal System; Zygomatic bone; allodynia; animal model development; attenuation; chronic pain; cytokine; dorsal horn; gamma-Aminobutyric Acid; injured; interdisciplinary approach; nerve injury; orofacial; painful neuropathy; public health relevance; receptor

DESCRIPTION (provided by applicant): The development of animal models of persistent pain has advanced our knowledge of the initiation of pain hypersensitivity due to sensitization of peripheral nociceptors and neurons in the medullary and spinal dorsal horns as well as other sites in the central nervous system (CNS). It is now commonly proposed that the initiation of this plasticity and resultant pain amplification is dependent upon activation of peripheral nociceptors. It is assumed that peripheral mechanisms are also responsible for the maintenance of the pain hypersensitivity, though the findings in this area are less compelling. Recent findings suggest that behavioral hyperalgesia following injury persists despite a reduction in peripheral neuronal activity suggesting that peripheral drive may be necessary but not sufficient for the maintenance of pain hypersensitivity after injury. The primary aim of this proposal is to study the mechanisms that underlie the maintenance of pain amplification after injury and to determine whether there are CNS mechanisms that participate in pain chronicity and how persistent pain emerges from the more acute stage after injury. Current animal models are not entirely adequate for the study of the chronicity and maintenance of pain hypersensitivity. We have developed two new models in the trigeminal system: a tendomyositis model of the masseter muscle and a neuropathic pain model of the infraorbital nerve. Both models exhibit long-term hyperalgesia/allodynia that is constant and lasts for months, and the inflammation due to the surgical procedure can be separated with the use of long-duration local anesthetics. Our major hypothesis is that tissue and nerve injury in the orofacial region can lead to the maintenance of secondary hyperalgesia that involves the activation CNS descending mechanisms and is less dependent on the peripheral drive associated with the injured target. The following Specific Aims will test these hypotheses using multidisciplinary approaches. #1: Test the hypothesis that the maintenance of long-term hyperalgesia after injury involves an attenuation of peripheral afferent drive and a transition to central mechanisms. #2: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory or a reduction of descending inhibitory inputs. #3: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory drive involving activation of trigeminal non-neural glial cells and their release of cytokines. #4: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory drive that involves shifts in the anionic reversal potential of trigeminal GABA-responsive neurons and a reduction in GABAA-induced inhibitory tone. #5: Test the hypothesis that the maintenance of long-term mechanical hyperalgesia is dependent upon rostral ventromedial medulla activation of a trigeminal brain stem interactive signaling cascade of 5-HT3, GABAA and NMDA receptors as well as glia and cytokines. PUBLIC HEALTH RELEVANCE: The major goal of the proposed research is to study the central nervous system mechanisms that account for the chronicity of persistent orofacial pain after tissue or nerve injury. Although it is now commonly proposed that the initiation of injury-induced neural plasticity and resultant pain amplification is dependent upon activation of peripheral nociceptors, it is unclear whether peripheral mechanisms are also responsible for the maintenance and chronicity of pain hypersensitivity and how persistent pain emerges from the more acute stage after injury. Our findings will lead to a transformative shift in the search for unique treatment approaches for persistent pain.

描述（由申请人提供）：持续性疼痛的动物模型的发展使我们对疼痛超敏反应的了解，这是由于髓质和脊髓背角以及中枢神经系统中其他部位（CNS）（CNS）的其他部位的外周伤害感受器和神经元的敏感性。现在通常提出，这种可塑性和由此导致的疼痛放大取决于周围伤害感受器的激活。假定外围机制也负责维持疼痛超敏反应，尽管该地区的发现不那么引人注目。最近的发现表明，尽管周围神经元活性降低，但受伤后的行为痛觉过敏仍然存在，这表明外周驱动可能是必要的，但不足以维持受伤后的疼痛超敏。该提案的主要目的是研究受伤后维持疼痛扩增的机制，并确定是否存在参与疼痛慢性的中枢神经系统机制，以及如何从受伤后更急性阶段出现持续性疼痛。当前的动物模型不足以研究疼痛超敏反应的慢性和维持。我们已经在三叉神经系统中开发了两个新模型：咬肌的肌病模型和胸神经的神经性疼痛模型。这两种模型均表现出长期的痛觉过敏/异常性症，持续数月持续，并且由于使用长期局部麻醉剂，可以将由于手术程序引起的炎症分离。我们的主要假设是，口面区域的组织和神经损伤可以导致涉及激活中枢神经系统降低机制的继发性痛觉过敏的维持，并且较少依赖于与受伤目标相关的外围驱动。以下特定目标将使用多学科方法检验这些假设。 ＃1：检验以下假设：受伤后长期痛觉过敏的维持涉及外围传入驱动器的衰减和向中心机制的过渡。 ＃2：检验以下假设：长期痛觉过敏的维持取决于降低促进性的增强或降低抑制投入的降低。 ＃3：检验以下假设：长期痛觉过敏的维持取决于涉及三叉神经神经胶质细胞激活的降低促进驱动器的增强及其细胞因子的释放。 ＃4：检验以下假设：长期性痛觉过敏的维持取决于降低促进驱动的增强，涉及三叉神经GABA响应性神经元的阴离子反转潜力以及GABAA诱导的抑制性抑制作用的降低。 ＃5：检验以下假设：长期机械性痛觉过敏的维持取决于5-HT3，GABAA和NMDA受体的三叉神经脑干茎互动信号级联的鼻腹侧髓质激活以及神经胶质和细胞因子。 公共卫生相关性：拟议的研究的主要目标是研究中枢神经系统机制，这些机制解释了组织或神经损伤后持续性口面疼痛的慢性。尽管现在通常提出的是，损伤引起的神经可塑性和导致的疼痛扩增取决于周围伤害感受器的激活，但尚不清楚周围机制是否也导致疼痛高压疼痛的维持和长期造成疼痛的慢性以及在受伤后急性较高的疼痛中如何持续出现。我们的发现将导致寻找持续疼痛的独特治疗方法的变革转变。