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

Xin Liu, Chilman Bae, Bolong Liu, Yong Mei Zhang, Xiangfu Zhou, Donghang Zhang, Cheng Zhou, Adriana DiBua, Livia Schutz, Martin Kaczocha, Michelino Puopolo, Terry P. Yamaguchi, Jin Mo Chung, Shao-Jun Tang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)767-779
Number of pages13
JournalMolecular Psychiatry
Issue number2
StatePublished - Feb 2023
Externally publishedYes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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