Opioids in pain control by M2 macrophages and M2 microglia

慢性疼痛，如由神经损伤引起的疼痛，与慢性神经炎症有关，包括外周和中枢神经系统（CNS）。事实上，巨噬细胞和中枢神经系统小胶质细胞等外周免疫细胞参与了疼痛的病理生理。目前的研究主要集中在这些细胞对疼痛发病机制的贡献上。本项目的主要目的是研究巨噬细胞和小胶质细胞在外周和中枢神经系统中的疼痛抑制作用。我们建议，不是一般的神经炎症抑制，而是促进内在抗炎M2巨噬细胞和M2小胶质细胞的有益作用，更有希望控制慢性疼痛。我们假设巨噬细胞和小胶质细胞在抗炎细胞因子白介素-4 （IL-4）的作用下向抗炎M2表型倾斜，将导致涉及内源性阿片系统的镇痛。具体来说，我们假设IL-4通过巨噬细胞和小胶质细胞中的IL-4受体作用，将巨噬细胞和小胶质细胞从M1表型转变为M2表型，并分别导致损伤神经和脊髓中M2细胞内水平升高和阿片肽释放增强。分泌的阿片样物质会激活外周或脊髓阿片样受体，改善神经损伤引起的机械和热超敏反应。在一系列的体内和密切相关的离体实验中，我们将使用急性分离的纯化巨噬细胞和小胶质细胞，研究阿片肽和受体对il -4诱导的镇痛、免疫细胞组成、巨噬细胞和小胶质细胞的M1/M2状态、它们的阿片肽含量和阿片受体表达的贡献，以及坐骨神经损伤引起的神经性疼痛小鼠模型中的直接疼痛抑制作用。总之，我们将探讨细胞因子不是唯一的介质，而是阿片系统与周围和中枢神经系统中IL-4和M2细胞的镇痛作用有关的观点。除了对基础研究和转化研究感兴趣的疼痛专家外，这些研究可能与免疫学家，神经生物学家和临床科学家研究IL-4和M2细胞在神经退行性疾病中的作用有关，因为阿片系统也可能参与这些中枢神经系统炎症状况。

Chronic pain such as pain resulting from nerve damage is associated with chronic neuroinflammation, in both peripheral and central nervous system (CNS). Indeed, peripheral immune cells such as macrophages and CNS microglia are involved in pain pathophysiology. Current research predominately focuses on the contribution of these cells to pain pathogenesis. The main objective of this project is to examine pain-inhibiting actions of macrophages and microglia in the peripheral and central nervous system. We propose that not the general inhibition of neuroinflammation, but fostering the beneficial effects of intrinsic anti-inflammatory M2 macrophages and M2 microglia is more promising for the control of chronic pain. We hypothesize that skewing macrophages and microglia toward an anti-inflammatory M2 phenotype in response to anti-inflammatory cytokine interleukin-4 (IL-4) will result in analgesia involving the endogenous opioid system. Specifically, we postulate that IL-4 acting via IL-4 receptors in macrophages and microglia will shift them from M1 to M2 phenotype, and will lead to elevated intracellular levels and enhanced release of opioid peptides from M2 cells at the injured nerves and in the spinal cord, respectively. The secreted opioids will activate peripheral or spinal opioid receptors to ameliorate mechanical and heat hypersensitivity triggered by nerve damage. In a series of in vivo and closely-related ex vivo experiments using acutely isolated purified macrophages and microglia, we will examine the contribution of opioid peptides and receptors to IL-4-induced analgesia, immune cell composition, M1/M2 status of macrophages and microglia, their opioid peptide content and opioid receptor expression, and direct pain-inhibiting actions in a mouse model of neuropathic pain induced by the sciatic nerve injury. In summary, we will explore the idea that cytokines are not the sole mediators, but that the opioid system is relevant to analgesic actions of IL-4 and M2 cells in the peripheral and central nervous system. In addition to pain specialists interested in basic and translational research, these studies may be relevant to immunologists, neurobiologists and clinical scientists studying the role of IL-4 and M2 cells in neurodegenerative diseases, as the opioid system may also be involved in these CNS neuroinflammatory conditions.