Neuroimmune interactions regulating the balance between remission and relapse of pain

神经免疫相互作用调节疼痛缓解和复发之间的平衡

• 批准号: 10613542
• 负责人: Geoffroy O Laumet
• 金额: $ 41.91万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613542
• 关键词: Absence of pain sensation; Acute Pain; Affect; Analgesics; Animals; Anti-Inflammatory Agents; Antibodies; Biochemistry; Calcium; Cells; Characteristics; Cytokine Receptors; Data; Disease remission; Dose; Down-Regulation; Equilibrium; Event; Exhibits; FDA approved; Flow Cytometry; Fostering; Gene Expression; Gene Expression Regulation; Genes; Goals; Image; Immune; Immunoassay; Individual; Interleukin-10; Interleukins; Intervention; Knowledge; Maintenance; Mediating; Modeling; Neuroimmune; Neuronal Plasticity; Nociception; Opioid; Opioid Receptor; Opioid agonist; Pain; Pain Research; Pain management; Patients; Persistent pain; Population; Postoperative Period; Receptor Signaling; Recovery; Recurrence; Recurrent pain; Regulation; Relapse; Research; Role; Signal Pathway; Signal Transduction; Source; Spinal; Spinal Cord; Spinal Ganglia; Surgical incisions; System; Testing; Thinking; Transgenic Mice; Up-Regulation; Vertebral column; chemotherapy; chronic pain; chronic pain patient; clinical practice; delta opioid receptor; dorsal horn; endogenous opioids; experience; genetic signature; innovation; insight; interleukin-10 receptor; magnetic beads; mouse model; neuroinflammation; new therapeutic target; novel; novel therapeutic intervention; pain chronification; pain model; pain sensitivity; painful neuropathy; patch clamp; pharmacologic; prevent; public health relevance; relapse prevention; spontaneous pain; therapeutic development; transcriptome sequencing

Persistent pain is common and debilitating. Long after apparent remission of the pain initiated by the primary insult, some patients experience relapse and recurrent episodes of severe pain. The long-term goal of this project is to decipher mechanisms that regulate the balance between remission and relapse of pain. Understanding these mechanisms will help to identify new therapeutic strategies to prevent the transition from acute to chronic pain and reduce the use of opioid for treatment of pain. We have developed a new mouse model to study the remission and relapse of pain. After a primary insult (surgical incision or a short dose of chemotherapy), a short period of pain (acute pain) is followed by remission in which pain sensitivity is absent. However, during remission pain can be reinstated by inhibition of anti-inflammatory cytokine or opioid receptor signaling, neither of which affect pain sensitivity in naive animals. Our preliminary data show that interleukin (IL)-10 is permanently upregulated during remission from pain and keeps neuroinflammation silent and upregulates δ-opioid receptor (δOR) gene expression and analgesic effects. This suggests that remission is a sensitized state that results from long-term neuroplasticity in the nociceptive system, which if inhibited will trigger relapse of pain. Our long-term goal is to switch transient remission to permanent recovery. Towards this goal, the central hypothesis of our proposal is that persistent IL-10 signaling is necessary to prevent the relapse to pain by keeping neuroinflammation silent and facilitating the activation of the endogenous opioid system. Thus, we will test this hypothesis with 2 specific aims. Our first aim will test the hypothesis that IL-10 signaling acts as a “brake” to keep neuroinflammation latent and prevents relapse to pain. Our second aim will investigate the hypothesis that relapse is prevented because IL-10 signaling promotes upregulation of gene expression and functional activation of δOR in the DRG. This proposal will fill critical gaps of knowledge on the roles of neuroimmune and immune-opioid crosstalk in chronic pain. Because regulation of the remission and relapse of pain has not been investigated previously, our model of pain recurrence can transform our knowledge on long lasting nociceptive plasticity in chronic pain. Ultimately, it could transform clinical practices by treating patients in remission to prevent the relapse of pain.

持续性疼痛很常见，而且会使人衰弱。在疼痛明显缓解很久之后， 一些患者经历了严重疼痛的复发和反复发作。的 这个项目的长期目标是破译调节平衡的机制， 疼痛的缓解和复发。了解这些机制将有助于确定新的 治疗策略，以防止从急性过渡到慢性疼痛，并减少使用 阿片类药物用于治疗疼痛。我们已经开发了一种新的小鼠模型来研究缓解， 疼痛复发。在原发性损伤（手术切口或短剂量化疗）后， 疼痛期（急性疼痛）之后是疼痛敏感性消失的缓解期。然而，在这方面， 在缓解期间，通过抑制抗炎细胞因子或阿片样物质， 受体信号传导，两者都不影响幼稚动物的疼痛敏感性。我们的初步数据 显示白细胞介素（IL）-10在疼痛缓解期间永久性上调， 神经炎症沉默和上调δ-阿片受体（δOR）基因表达和镇痛 方面的影响. 这表明，缓解是一种敏感状态，是长期神经可塑性的结果， 伤害感受系统，如果受到抑制，将引发疼痛复发。我们的长期目标是 从暂时缓解到永久恢复。为了实现这一目标， 我们的建议是，持续的IL-10信号传导是防止疼痛复发所必需的， 保持神经炎症沉默并促进内源性阿片样物质的激活 系统因此，我们将用两个具体目标来检验这个假设。我们的第一个目标是测试 假设IL-10信号传导充当“刹车”，以保持神经炎症潜伏并防止 疼痛复发。我们的第二个目标将调查复发被预防的假设 因为IL-10信号传导促进基因表达的上调和 DRG中的δOR。这项建议将填补关键的知识空白的作用，神经免疫 和慢性疼痛中的免疫-阿片样物质串扰。 因为以前没有研究过疼痛缓解和复发的调节， 我们的疼痛复发模型可以改变我们对长期伤害性可塑性的认识， 慢性疼痛最终，它可以通过治疗缓解期患者来改变临床实践 防止疼痛复发