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

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.

References

  1. Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 2019;393:1558–68.

    Article  PubMed  Google Scholar 

  2. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–74.

    Article  CAS  PubMed  Google Scholar 

  3. Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10:537–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, et al. Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med. 2017;23:164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci: Off J Soc Neurosci. 1994;14:2301–12.

    Article  CAS  Google Scholar 

  6. Angst Martin S, Clark JD. Opioid-induced Hyperalgesia: A Qualitative Systematic Review. Anesthesiology 2006;104:570–87.

    Article  CAS  PubMed  Google Scholar 

  7. Chu LF, Angst MS, Clark D. Opioid-induced Hyperalgesia in Humans: Molecular Mechanisms and Clinical Considerations. Clin J Pain. 2008;24:479–96. 1097/AJP.1090b1013e31816b31812f31843

    Article  PubMed  Google Scholar 

  8. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14:145–61.

    Article  PubMed  Google Scholar 

  9. Roeckel L-A, Le Coz G-M, Gavériaux-Ruff C, Simonin F. Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience 2016;338:160–82.

    Article  CAS  PubMed  Google Scholar 

  10. Drdla R, Gassner M, Gingl E, Sandkühler J. Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal. Science 2009;325:207–10.

    Article  CAS  PubMed  Google Scholar 

  11. Ferrini F, Trang T, Mattioli T-AM, Laffray S, Del’Guidice T, Lorenzo L-E, et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat Neurosci. 2013;16:183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu X, Liu BL, Yang Q, Zhou X, Tang SJ. Microglial ablation does not affect opioid-induced hyperalgesia in rodents. Pain 2022;163:508–17.

    Article  CAS  PubMed  Google Scholar 

  13. Berta T, Liu YC, Xu ZZ, Ji RR. Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience 2013;247(Supplement C):376–85.

    Article  CAS  PubMed  Google Scholar 

  14. Sanna MD, Ghelardini C, Galeotti N. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia. Pain 2015;156:1265–75.

    Article  CAS  PubMed  Google Scholar 

  15. Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.

    Article  CAS  PubMed  Google Scholar 

  16. Ji R-R, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20:667–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barres BA. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 2008;60:430–40.

    Article  CAS  PubMed  Google Scholar 

  18. Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18:942–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Allen NJ, Eroglu C. Cell Biology of Astrocyte-Synapse Interactions. Neuron 2017;96:697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lines J, Martin ED, Kofuji P, Aguilar J, Araque A. Astrocytes modulate sensory-evoked neuronal network activity. Nat Commun. 2020;11:3689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, et al. Fulminant Jejuno-Ileitis following Ablation of Enteric Glia in Adult Transgenic Mice. Cell 1998;93:189.

    Article  CAS  PubMed  Google Scholar 

  22. Miyoshi H, Ajima R, Luo CT, Yamaguchi TP, Stappenbeck TS. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 2012;338:108–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 2001;15:859–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999;23:99.

    Article  CAS  PubMed  Google Scholar 

  25. Ho H-YH, Susman MW, Bikoff JB, Ryu YK, Jonas AM, Hu L, et al. Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci. 2012;109:4044–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Garcia ADR, Doan NB, Imura T, Bush TG, Sofroniew MV. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci. 2004;7:1233.

    Article  CAS  PubMed  Google Scholar 

  27. Callahan BL, Gil AS, Levesque A, Mogil JS Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J Pain. 2008; 9:174–84.

  28. Andrews N, Loomis S, Blake R, Ferrigan L, Singh L, McKnight AT. Effect of gabapentin-like compounds on development and maintenance of morphine-induced conditioned place preference. Psychopharmacol (Berl). 2001;157:381–7.

    Article  CAS  Google Scholar 

  29. Bae C, Wang J, Shim HS, Tang S-J, Chung JM, La J-H. Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice. Mol Pain. 2018;14:1744806918797032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee KY, Bae C, Lee D, Kagan Z, Bradley K, Chung JM, et al. Low-intensity, Kilohertz Frequency Spinal Cord Stimulation Differently Affects Excitatory and Inhibitory Neurons in the Rodent Superficial Dorsal Horn. Neuroscience 2020;428:132–9.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang D, Wei Y, Liu J, Chen H, Li J, Zhu T, et al. Single-nucleus transcriptomic atlas of spinal cord neuron in human. bioRxiv. 2021: 2021.2009.2028.462103.

  32. Zhang D, Wei Y, Liu J, Yang Y, Ou M, Chen Y, et al. Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse. bioRxiv. 2022: 2022.2002.2015.480622.

  33. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res. 2001;86:56–62.

    Article  CAS  PubMed  Google Scholar 

  34. Stoicea N, Russell D, Weidner G, Durda M, Joseph NC, Yu J, et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharm. 2015;6:104.

    Article  Google Scholar 

  35. Song P, Zhao ZQ. The involvement of glial cells in the development of morphine tolerance. Neurosci Res. 2001;39:281–6.

    Article  CAS  PubMed  Google Scholar 

  36. Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, et al. Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience 2010;167:880–93.

    Article  CAS  PubMed  Google Scholar 

  37. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 1999;23:297–308.

    Article  CAS  PubMed  Google Scholar 

  38. Punnakkal P, von Schoultz C, Haenraets K, Wildner H, Zeilhofer HU. Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn. J Physiol. 2014;592:759–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Todd AJ. Identifying functional populations among the interneurons in laminae I-III of the spinal dorsal horn. Mol Pain. 2017;13:1744806917693003.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yuan S, Shi Y, Tang SJ Wnt Signaling in the Pathogenesis of Multiple Sclerosis-Associated Chronic Pain. J Neuroimmune Pharmacology 2012; https://doi.org/10.1007/s11481-012-9370-3.

  41. Yuan S, Ji G, Li B, Andersson T, Neugebauer V, Tang S-J. A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain. Pain 2015;156:1311–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Simonetti M, Kuner R. Spinal Wnt5a Plays a Key Role in Spinal Dendritic Spine Remodeling in Neuropathic and Inflammatory Pain Models and in the Proalgesic Effects of Peripheral Wnt3a. J Neurosci: Off J Soc Neurosci. 2020;40:6664–77.

    Article  CAS  Google Scholar 

  43. Li B, Shi Y, Shu J, Gao J, Wu P, Tang S-J. Wingless-type Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Regulates Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Glycoprotein 120 (gp120)-induced Expression of Pro-Inflammatory Cytokines via the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and c-Jun N-terminal Kinase (JNK) Signaling Pathways. J Biol Chem. 2013;288:13610–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shi Y, Yuan S, Li B, Wang J, Carlton S, Chung K, et al. Regulation of Wnt signaling by nociceptive input in animal models. Mol Pain. 2012;8:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li Y, Li B, Wan X, Zhang W, Zhong L, Tang S-J. NMDA receptor activation stimulates transcription-independent rapid wnt5a protein synthesis via the MAPK signaling pathway. Mol Brain. 2012;5:1.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chen J, Park CS, Tang SJ. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem. 2006;281:11910–6.

    Article  CAS  PubMed  Google Scholar 

  47. Shi Y, Yuan S, Tang S-J. Morphine and HIV-1 gp120 cooperatively promote pathogenesis in the spinal pain neural circuit. Mol Pain. 2019;15:1744806919868380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yuan S, Shi Y, Guo K, Tang S-J. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice. J. Neuroimmune Pharmacol. 2018;13:230–6.

  49. Zhuang Z-Y, Wen Y-R, Zhang D-R, Borsello T, Bonny C, Strichartz GR, et al. A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance. J Neurosci. 2006;26:3551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci: Off J Soc Neurosci. 2004;24:7353–65.

    Article  CAS  Google Scholar 

  51. Hilla AM, Diekmann H, Fischer D. Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury. J Neurosci. 2017;37:6113–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Janova H, Arinrad S, Balmuth E, Mitjans M, Hertel J, Habes M, et al. Microglia ablation alleviates myelin-associated catatonic signs in mice. J Clin Inv. 2017;128:734–45.

  53. Reshef R, Kudryavitskaya E, Shani-Narkiss H, Isaacson B, Rimmerman N, Mizrahi A, et al. The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. eLife. 2017;6:e30809.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Oliva AA, Jiang M, Lam T, Smith KL, Swann JW. Novel Hippocampal Interneuronal Subtypes Identified Using Transgenic Mice That Express Green Fluorescent Protein in GABAergic Interneurons. J Neurosci. 2000;20:3354–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schroder K, Tschopp J. The Inflammasomes. Cell 2010;140:821–32.

    Article  CAS  PubMed  Google Scholar 

  56. Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, et al. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008;22:1178–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci. 2016;113:E3441–E3450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, et al. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells. 2003;8:645–54.

    Article  CAS  PubMed  Google Scholar 

  59. Song N, Li T. Regulation of NLRP3 Inflammasome by Phosphorylation. Front Immunol. 2018;9:2305.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Servick K. Primed for pain. Science 2016;354:569–71.

    Article  CAS  PubMed  Google Scholar 

  61. Araldi D, Khomula EV, Ferrari LF, Levine JD. Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. J Neurosci. 2018;38:2226–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen Y, Moutal A, Navratilova E, Kopruszinski C, Yue X, Ikegami M, et al. The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. Sci Transl Med. 2020;12:eaay7550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu X, Bae C, Gelman B, Chung JM, Tang S-J Mechanism and role of astrogliosis in the pathogenesis of HIV-associated pain. bioRxiv 2021: 2021.2004.2028.441838.

  64. Prescott SA, Sejnowski TJ, De, Koninck Y. Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain. 2006;2:32.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ahmadi S, Lippross S, Neuhuber WL, Zeilhofer HU. PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci. 2002;5:34–40.

    Article  CAS  PubMed  Google Scholar 

  66. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci: Off J Soc Neurosci. 2002;22:6724–31.

    Article  CAS  Google Scholar 

  67. Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134:1127–39.

  68. Ohmichi M, Ohmichi Y, Ohishi H, Yoshimoto T, Morimoto A, Li Y, et al. Activated spinal astrocytes are involved in the maintenance of chronic widespread mechanical hyperalgesia after cast immobilization. Mol. Pain. 2014;10:6.

  69. Sasaki M, Kamiya Y, Bamba K, Onishi T, Matsuda K, Kohno T, et al. Serotonin Plays a Key Role in the Development of Opioid-Induced Hyperalgesia in Mice. J Pain. 2021;22:715–29.

  70. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.

    Article  PubMed  Google Scholar 

  71. Kao S-C, Zhao X, Lee C-Y, Atianjoh FE, Gauda EB, Yaster M, et al. Absence of μ opioid receptor mRNA expression in astrocytes and microglia of rat spinal cord. Neuro Report. 2012;23:378–84. https://doi.org/10.1097/WNR.1090b1013e3283522e3283521b

    CAS  Google Scholar 

  72. Stiene-Martin A, Zhou R, Hauser KF. Regional, developmental, and cell cycle-dependent differences in mu, delta, and kappa-opioid receptor expression among cultured mouse astrocytes. Glia 1998;22:249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stiene-Martin A, Gurwell JA, Hauser KF. Morphine alters astrocyte growth in primary cultures of mouse glial cells: evidence for a direct effect of opiates on neural maturation. Brain Res Dev Brain Res. 1991;60:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ikeda H, Miyatake M, Koshikawa N, Ochiai K, Yamada K, Kiss A, et al. Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation. J Biol Chem. 2010;285:38415–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gong G, Hu L, Qin F, Yin L, Yi X, Yuan L, et al. Spinal WNT pathway contributes to remifentanil induced hyperalgesia through regulating fractalkine and CX3CR1 in rats. Neurosci Lett. 2016;633:21–27.

    Article  CAS  PubMed  Google Scholar 

  76. Nomachi A, Nishita M, Inaba D, Enomoto M, Hamasaki M, Minami Y. Receptor Tyrosine Kinase Ror2 Mediates Wnt5a-induced Polarized Cell Migration by Activating c-Jun N-terminal Kinase via Actin-binding Protein Filamin A. J Biol Chem. 2008;283:27973–81.

    Article  CAS  PubMed  Google Scholar 

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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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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 (2022). https://doi.org/10.1038/s41380-022-01815-0

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