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: 8452236
• 负责人: Gregory Corder
• 金额: $ 1.71万
• 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 2013-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452236
• 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:

描述（由申请人提供）：外周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。疼痛的强度和性质由原伤害感受系统与代偿性内源性抑制系统（即脊髓阿片样物质信号传导）之间的净平衡决定。有趣的是，一小组研究表明，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性感受的抑制仍然存在。例如，阿片受体拮抗剂使异常性疼痛恢复。这就引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。第二，在没有明显的超敏反应行为迹象的情况下，潜在的伤害性致敏是否会持续存在？我的初步数据表明，纳洛酮，当鞘内注射数周至数月后，足底CFA，恢复超敏反应的行为体征和诱导背角ERK磷酸化。两者都被脊髓NMDA受体拮抗作用所阻断。我的中心假设是，外周炎症诱导中枢神经系统阿片样物质通路（Aim 1）的信号传导延长，从而掩盖了原伤害感受性NMDA和AMPA信号传导（Aim 2）。该F31提案试图更好地表征被内源性阿片活性掩盖的潜在致敏作用的机制。目的1检验脊髓阿片能信号传导强直性掩盖伤害性敏化的假设。目标1A调查了？阿片受体亚型与选择性拮抗剂的使用。目的利用离体脊髓切片GTP？分别进行S35结合测定和鞘内隔离阿片肽抗血清。目的1D检验阿片受体阻断剂阻断强直性传入伤害性感受的假说。在目标2中，我将测试这一想法，即多巴胺能信号驱动随后的超敏反应 脊髓阿片受体阻滞，重点是脊髓NMDA（Aim 2A）和AMPA/红藻氨酸受体（Aim 2B）。通过更好地了解持久的阿片类镇痛作用，该项目可以为未来增强慢性疼痛患者内源性阿片类镇痛的策略铺平道路，从而具有揭示新靶点以防止急性疼痛向慢性疼痛转变的长期潜力。这个F31奖将帮助我实现我的目标，使我能够成功地竞争强大的博士后职位，并最终在研究科学和教学方面取得成功的职业生涯，并在强大的医学研究型大学环境中获得终身职位：