Glial IL-33 signaling through an ST2-to-CXCL12 pathway in the spinal cord contributes to morphine-induced hyperalgesia and tolerance

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.