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.

中文翻译：

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通过脊髓中 ST2 到 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

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，吗啡引起的痛觉过敏和镇痛耐受性阻碍了患者的持久疗效。在这里，我们研究了这种现象的潜在分子机制。我们发现在小鼠中反复皮下注射吗啡会增加主要在少突胶质细胞和星形胶质细胞中的细胞因子白细胞介素 33 (IL-33) 的丰度及其主要在星形胶质细胞中的受体 ST2 的丰度。脊髓中 IL-33 或 ST2 的药理学抑制或敲低减弱了吗啡诱导的小鼠痛觉过敏和镇痛耐受性，Il33或St2的整体敲除也是如此，这也减少了吗啡增强的星形胶质细胞激活和兴奋性突触传递。此外，通过促进脊髓中趋化因子 CXCL12 的产生，IL-33 介导的痛觉过敏和耐受需要由肿瘤坏死因子受体相关因子 6 (TRAF6) 和星形胶质细胞中的激酶 JNK 介导的途径。研究结果表明，靶向 IL-33-ST2 信号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。