Glial IL-33 signaling through an ST2-to-CXCL12 pathway in the spinal cord contributes to morphine-induced hyperalgesia and tolerance
Glial IL-33 signaling through an ST2-to-CXCL12 pathway in the spinal cord contributes to morphine-induced hyperalgesia and tolerance
复制标题
脊髓中通过 ST2 至 CXCL12 通路的胶质细胞 IL-33 信号传导有助于吗啡诱导的痛觉过敏和耐受
DOI：
10.1126/scisignal.abe3773
复制
发表时间：
2021-09-07
影响因子：
7.3
通讯作者：
Mi, Wen-Li
中科院分区：
文献类型：
--
作者：
Hu, Xue-Ming;Yang, Wei;Mi, Wen-Li
阻断阿片类药物诱导的星形胶质细胞趋化因子释放可能改善长期疼痛管理。星形胶质细胞减弱阿片类药物吗啡和其他阿片类药物对治疗疼痛非常有效。然而，它们的长期使用可能导致耐受性，甚至矛盾地增加患者的疼痛。Hu等人发现，吗啡诱导的耐受和痛觉过敏的这种现象部分是由星形胶质细胞的自分泌IL-33信号传导和脊柱中少突胶质细胞的旁分泌IL-33信号传导介导的。用吗啡治疗小鼠增加了IL-33及其受体ST 2的丰度，从而激活了星形胶质细胞趋化因子CXCL 12的产生和释放。在星形胶质细胞中特异性地抑制这一通路，或者阻断趋化因子受体CXCR 4抑制吗啡诱导的小鼠痛觉过敏。研究结果表明，靶向这一途径可能会提高阿片类药物在疼痛管理中的长期疗效。吗啡和其他阿片类药物对治疗中度至重度疼痛非常有效。然而，吗啡诱导的痛觉过敏和镇痛耐受阻止患者的持久疗效。在这里，我们研究了这种现象的潜在分子机制。我们发现，反复皮下注射吗啡在小鼠中增加的细胞因子白细胞介素-33（IL-33）的丰度主要在少突胶质细胞和星形胶质细胞，其受体ST 2主要在星形胶质细胞。药理学抑制或敲低脊髓中的IL-33或ST 2减弱了小鼠中吗啡诱导的痛觉过敏和镇痛耐受，如全面敲除IL-33或ST 2，这也减少了吗啡增强的星形胶质细胞活化和兴奋性突触传递。此外，由肿瘤坏死因子受体相关因子6（TRAF 6）和星形胶质细胞中的激酶JNK介导的途径是通过促进脊髓中趋化因子CXCL 12的产生来实现IL-33介导的痛觉过敏和耐受所必需的。研究结果表明，靶向IL-33-ST 2信号传导可以使阿片类药物在慢性疼痛管理中产生持续的镇痛作用。
Description Blocking opioid-induced chemokine release from astrocytes may improve long-term pain management. Astrocytes attenuate opioids Morphine and other opioids are highly effective for treating pain. However, their chronic use can lead to tolerance and even a paradoxical increase in pain in patients. Hu et al. found that this phenomenon of morphine-induced tolerance and hyperalgesia was mediated, in part, by autocrine IL-33 signaling by astrocytes and paracrine IL-33 signaling by oligodendrocytes in the spine. Treating mice with morphine increased the abundance of IL-33 and its receptor ST2, which consequently activated the production and release of the chemokine CXCL12 from astrocytes. Suppressing this pathway specifically in astrocytes or pharmacologically blocking the chemokine receptor CXCR4 dampened morphine-induced hyperalgesia in mice. The findings suggest that targeting this pathway may improve the long-term efficacy of opioids in pain management. Morphine and other opiates are highly effective for treating moderate to severe pain. However, morphine-induced hyperalgesia and analgesic tolerance prevent durable efficacy in patients. Here, we investigated the underlying molecular mechanisms of this phenomenon. We found that repeated subcutaneous injections of morphine in mice increased the abundance of the cytokine interleukin-33 (IL-33) primarily in oligodendrocytes and astrocytes and that of its receptor ST2 mainly in astrocytes. Pharmacological inhibition or knockdown of IL-33 or ST2 in the spinal cord attenuated morphine-induced hyperalgesia and analgesic tolerance in mice, as did global knockout of either Il33 or St2, which also reduced morphine-enhanced astroglial activation and excitatory synaptic transmission. Furthermore, a pathway mediated by tumor necrosis factor receptor–associated factor 6 (TRAF6) and the kinase JNK in astrocytes was required for IL-33–mediated hyperalgesia and tolerance through promoting the production of the chemokine CXCL12 in the spinal cord. The findings suggest that targeting IL-33–ST2 signaling could enable opioids to produce sustained analgesic effects in chronic pain management.