Neuroimmune interactions regulating the balance between remission and relapse of pain

持续性疼痛很常见，而且会使人虚弱。在明显缓解由以下原因引起的疼痛很久之后 最初的侮辱，一些患者经历了复发和反复发作的剧烈疼痛。这个 该项目的长期目标是破译机制，以调节 缓解和复发的疼痛。了解这些机制将有助于识别新的 防止从急性疼痛过渡到慢性疼痛并减少使用的治疗策略 治疗疼痛的阿片类药物。我们开发了一种新的小鼠模型来研究缓解和 疼痛复发。在初次伤害(手术切开或小剂量化疗)后，短期的 疼痛期(急性疼痛)之后是疼痛敏感期消失的缓解期。然而， 在缓解期间，可以通过抑制抗炎细胞因子或阿片类药物来恢复疼痛 受体信号，这两种信号都不会影响幼稚动物的疼痛敏感性。我们的初步数据 表明白介素10在疼痛缓解期间永久上调，并保持 神经炎症抑制和上调δ-阿片受体(δOR)基因表达与止痛药 效果。 这表明，缓解是一种敏感化状态，是长期神经可塑性的结果 伤害性感受系统，如果被抑制，会引发疼痛复发。我们的长期目标是 将暂时性缓解转为永久性恢复。为了实现这一目标，核心假设是 我们的建议是，持续的IL-10信号是必要的，以防止复发的疼痛通过 抑制神经炎症，促进内源性阿片类药物的激活 系统。因此，我们将用两个具体的目标来检验这一假设。我们的第一个目标是测试 假设IL-10信号起到“刹车”的作用，以保持神经炎症潜伏并预防 又回到了痛苦之中。我们的第二个目标是调查复发可以预防的假设。 因为IL-10信号促进血管内皮细胞基因表达上调和功能激活 δ或在DRG中。这项提议将填补有关神经免疫作用的关键知识空白。 慢性疼痛中免疫阿片类药物的串扰。 由于以前没有研究过疼痛缓解和复发的规律， 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 在慢性疼痛中。最终，它可以通过治疗缓解期的患者来改变临床实践。 以防止疼痛复发。

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.