Prolonged activation of endogenous opioid analgesia after inflammation

炎症后内源性阿片类镇痛作用的延长激活

• 批准号: 8320548
• 负责人: Gregory Corder
• 金额: $ 2.99万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320548
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; Absence of pain sensation; Acute; Afferent Neurons; Agonist; Animal Model; Animals; Antibodies; Attenuated; Behavior; Behavioral; Binding; Biological Assay; Brain; CTOP; Coupling; Cutaneous; Data; Dose; Dynorphins; Educational process of instructing; Enkephalins; Environment; Equilibrium; Female; Freund' s Adjuvant; Future; GTP-Binding Proteins; Glutamates; Goals; Guanosine Triphosphate; Heating; Human; Hyperalgesia; Hypersensitivity; Immune Sera; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intrathecal Injections; Kainic Acid Receptors; Lead; Light; Local anesthesia; Masks; Mechanics; Mediating; Medical Research; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Naltrexone; Neurons; Neurotransmitters; Nociception; Opioid; Opioid Peptide; Opioid Receptor; Pain; Pain quality; Pathway interactions; Peptides; Peripheral; Persistent pain; Phosphorylation; Positioning Attribute; Postdoctoral Fellow; Predoctoral Individual National Research Service Award; Presynaptic Terminals; Receptor Signaling; Research; Resolution; Science; Sensory Thresholds; Signal Transduction; Slice; Spinal; Spinal Anesthesia; Spinal Cord; Stimulus; Synapses; System; Testing; Therapeutic; Tissues; Touch sensation; Universities; allodynia; attenuation; career; central sensitization; chronic pain; design; dorsal horn; endogenous opioids; endomorphin 1; inflammatory pain; injured; kainate; male; meetings; naltrindole; neural circuit; neuronal excitability; norbinaltorphimine; novel; prevent; receptor; response; sciatic nerve; stressor; transmission process

DESCRIPTION (provided by applicant): Peripheral tissue inflammation can lead to maladaptive plasticity in the spinal cord and brain which contributes to persistent pain. The intensity and quality of pain is determined by the net balance between the activities of pronociceptive systems with compensatory endogenous inhibitory systems, namely spinal opioid signaling. Interestingly, a small set of studies indicate that endogenous opioid inhibition f acute nociception persists even after the initial signs of hyperalgesia have subsided. For example, opioid receptor antagonists reinstate allodynia. This raises two intriguing questions. First, opioid receptor subtypes and neural circuits remain unclear. Second, does a latent nociceptive sensitization persist in the absence of overt behavioral signs of hypersensitivity? My preliminary data show that naltrexone, when intrathecally administered weeks to months after intraplantar CFA, reinstated behavioral signs of hypersensitivity and induced dorsal horn ERK phosphorylation. Both were blocked by spinal antagonism of NMDA receptors. My central hypothesis is that peripheral inflammation induces prolonged signaling of CNS opioidergic-circuits (Aim 1) that mask pronociceptive NMDA and AMPA signaling (Aim 2). This F31 proposal attempts to better characterize the mechanisms that underlie the latent sensitization that is masked by endogenous opioid activity. Aim 1 tests the hypothesis that spinal opioidergic signaling tonically masks nociceptive sensitization. Aim 1A investigates ¿-, ¿-, and ?-opioid receptor subtypes with the use of selective antagonists. Aim 1B and 1C test mechanisms of constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTP ?S35 binding assay and intrathecal sequestering opioid peptide antiserum, respectively. Aim 1D tests the hypothesis that opioid receptor blockade disinhibits tonic afferent nociception. In Aim 2 I will test the idea that glutamatergic signaling drives the hypersensitivity that follows spinal opioid receptor blockade, with a focus on spinal NMDA (Aim 2A) and AMPA/kainate-receptors (Aim 2B). By better understanding long-lasting opioid antinociception, this project could pave the way for future strategies to enhance endogenous opioid analgesia in humans with chronic pain, and thus has the long-term potential to reveal novel targets to prevent the transition for acute to chronic pain. This F31 award will help me achieve my goals that will enable me to successfully compete for strong post-doctoral positions and ultimately, a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment: PUBLIC HEALTH RELEVANCE: Sensitization of pain pathways, in the setting of tissue inflammation, leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.

描述（由申请人提供）：周围组织炎症可导致脊髓和大脑的适应不良可塑性，从而导致持续性疼痛。疼痛的强度和质量取决于伤害感受系统的活动与补偿性内源性抑制系统（即脊髓阿片类药物信号传导）之间的净平衡。有趣的是，一小部分研究表明，即使在最初的痛觉过敏症状消退后，内源性阿片类药物对急性伤害感受的抑制仍然持续存在。例如，阿片受体拮抗剂可恢复异常性疼痛。这提出了两个有趣的问题。首先，阿片受体亚型和神经回路仍不清楚。其次，在没有明显的超敏反应行为迹象的情况下，潜在的伤害性敏感化是否持续存在？我的初步数据显示，在足底 CFA 后鞘内给药数周至数月时，纳曲酮可恢复超敏反应的行为症状并诱导背角 ERK 磷酸化。两者均被 NMDA 受体的脊髓拮抗作用所阻断。我的中心假设是，外周炎症会诱导中枢神经系统阿片受体信号传导时间延长（目标 1），从而掩盖伤害性 NMDA 和 AMPA 信号传导（目标 2）。该 F31 提案试图更好地描述内源性阿片类药物活性所掩盖的潜在致敏作用的机制。目标 1 检验脊髓阿片能信号传导强直性地掩盖伤害性敏化的假设。目标 1A 使用选择性拮抗剂研究 ¿-、 ¿- 和 β-阿片受体亚型。目标 1B 和 1C 分别使用离体脊髓切片 GTP ?S35 结合测定和鞘内隔离阿片肽抗血清测试组成型受体信号传导和强效阿片类药物释放的机制。目标 1D 检验阿片受体阻断可抑制强直传入伤害感受的假设。在目标 2 中，我将测试谷氨酸信号传导导致随后的超敏反应的想法 脊髓阿片受体阻断，重点是脊髓 NMDA（目标 2A）和 AMPA/红藻氨酸受体（目标 2B）。通过更好地了解长效阿片类药物镇痛作用，该项目可以为未来增强慢性疼痛人类内源性阿片类药物镇痛作用的策略铺平道路，从而具有揭示防止急性疼痛向慢性疼痛转变的新靶点的长期潜力。这个 F31 奖项将帮助我实现我的目标，使我能够成功竞争强有力的博士后职位，并最终在研究科学和教学领域取得成功的职业生涯，从在强大的医学研究大学环境中获得终身教职开始： 公共健康相关性：在组织炎症的情况下，疼痛通路的敏感性会导致超敏状态，这种状态可以通过补偿性内源性抑制系统来抵消。该项目旨在了解脊髓阿片类药物系统掩盖长期谷氨酸敏化的机制。旨在增强这种内源性阿片类信号传导的治疗策略可能会减少持续性疼痛的发生。