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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人证明）：周围组织炎症会导致脊髓绳索绳索中的疾病，而脑部的脑部将疼痛置于疼痛，并通过补偿性抑制系统（即脊柱信号传导，一组急性的急性发病率是急性的抗衰老，例如，阿片受体拮抗剂恢复了阿片类异肌潜在的致命主义者在没有过度的行为的情况下持续存在，我的初步数据表明，纳尔特雷酮的性能是高敏性和诱导性背horne horne erk磷酸化的迹象。）。 - ，¿ - 和使用脊髓的脊髓s35结合测定法和鞘内隔离的阿片类药物抗血清的替代性抗性的脊髓slice slice slice slice slice slice slice slice the the Matersitive to s s35结合测定法脊柱阿片受体阻滞，重点是脊柱NMDA（AIM 2A）和AMPA/Kainate-peptors（AIM 2B）长期对慢性疼痛过渡的潜在目标。强大的医学研究。