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Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

Molecular Psychiatry volume 28, pages 767–779 (2023)Cite this article

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Abstract

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.

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Fig. 1: Reactive astrocytes are critical for morphine-induced hyperalgesia.
Fig. 2: Reactive astrocytes are critical for morphine-induced NCP in the SDH.
Fig. 3: Neuronal Wnt5a is essential for morphine-induced astrogliosis, hyperalgesia, and NCP in the SDH.
Fig. 4: Astrocytic ROR2 is required for morphine-induced astrogliosis, hyperalgesia, and NCP in the SDH.
Fig. 5: Morphine induces IL-1β activation (cleavage) via Wnt5a-ROR2 signaling-dependent astrogliosis.
Fig. 6: IL-1Ra blocks OIH and NCP.
Fig. 7: The Wnt5a-ROR2 signaling pathway controls inflammasome activation during OIH development.
Fig. 8: Model of the neuron-to-astrocyte Wnt5a-ROR2 signaling pathway in OIH development.

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Acknowledgements

We are grateful for the productive discussion and insights from Dr. Ye Zhang. This work was supported by NIH grants R01NS079166 (SJT), R01DA036165 (SJT), R01NS095747 (SJT), 1R01DA050530 (SJT, JMC) and 1R01NS122571 (SJT). Subo Yuan participated in a part of behavioral testing experiments.

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Authors and Affiliations

  1. Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA

    Xin Liu, Adriana DiBua, Livia Schutz, Martin Kaczocha, Michelino Puopolo & Shao-Jun Tang

  2. Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA

    Xin Liu, Adriana DiBua, Livia Schutz, Martin Kaczocha, Michelino Puopolo & Shao-Jun Tang

  3. Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA

    Chilman Bae, Bolong Liu, Yong-Mei Zhang, Jin Mo Chung & Shao-Jun Tang

  4. School of Electrical, Computer, and Biomedical Engineering, Southern Illinois University, Carbondale, 62901, IL, USA

    Chilman Bae

  5. Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 W Tianhe Rd, Guangzhou, 510630, China

    Bolong Liu & Xiangfu Zhou

  6. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, China

    Yong-Mei Zhang

  7. Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China

    Donghang Zhang & Cheng Zhou

  8. Center for Cancer Research, Cancer and Developmental Biology Laboratory, Cell Signaling in Vertebrate Development Section, NCI-Frederick, NIH, Frederick, 21702, MD, USA

    Terry P. Yamaguchi

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  1. Xin Liu
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Contributions

Experimental design: SJT. Data collection and analysis: XL, CB, BL, DZ, CZ, YZ, AD, LS, MK, MP. Providing critical reagents: TPY. Manuscript preparation: XL, SJT, XZ, JMC, TPY.

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Correspondence to Shao-Jun Tang.

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Liu, X., Bae, C., Liu, B. et al. Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling. Mol Psychiatry 28, 767–779 (2023). https://doi.org/10.1038/s41380-022-01815-0

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