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Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing opioid analgesia

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Abstract

Heroin use disorder in humans and chronic opioid administration to mice result in an increase in the number and a decrease in the size of detected hypocretin (Hcrt, or orexin) neurons. Chronic morphine administration to mice increases Hcrt axonal projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase (TH) in VTA and the number of detected TH+ cells in VTA, and activates VTA and hypothalamic microglia. Co-administration of morphine with the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, the increase in Hcrt projections to the VTA and microglial activation in the VTA and hypothalamus. Co-administration of suvorexant with morphine also prevents morphine anticipatory behavior and reduces opioid withdrawal symptoms. However, suvorexant does not diminish morphine analgesia. Here we show that combined administration of opioids and suvorexant may reduce the addiction potential of opioid use for pain relief in humans while maintaining the analgesic effects of opioids.

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Fig. 1: Involvement of opioid receptors in the increased number of detected Hcrt neurons and the shrinkage in Hcrt neuron size caused by opioids.
Fig. 2: Chronic opioid administration does not induce Hcrt expression in non-Hcrt neurons.
Fig. 3: Suvorexant blocked changes in Hcrt cell number and size produced by morphine.
Fig. 4: Suvorexant blocked microglial activation in the hypothalamus and VTA.
Fig. 5: Effect of chronic morphine on Hcrt projections, TH levels and TH cell number in VTA and SN.
Fig. 6: Hcrt receptor blockade prevents conditioned morphine anticipation of daily morphine injection.

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Data availability

All data presented in this work have been deposited in G-Node (https://gin.g-node.org/fmfwu/Siegel_NatureMH_2024) and are available without restrictions from the corresponding author.

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Acknowledgements

Support: DA034748 to J.M.S., DA058639 to J.M.S, HL148574 to J.M.S and the Medical Research Service of the Department of Veterans Affairs to J.M.S. A preprint of some of this work has been published (R. McGregor, M.-F. Wu, T. C. Thannickal & J. M. Siegel, Preprint at bioRxiv https://doi.org/10.1101/2023.09.22.559044 (2023). Opiate anticipation, opiate induced anatomical changes in hypocretin (Hcrt, orexin) neurons and opiate induced microglial activation are blocked by the dual Hcrt receptor antagonist suvorexant, while opiate analgesia is maintained. bioRxiv 559044v1, PMC10542511).

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  1. These authors contributed equally: Ronald McGregor, Ming-Fung Wu.

Authors and Affiliations

  1. Neuropsychiatric Institute and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA

    Ronald McGregor, Ming-Fung Wu, Thomas C. Thannickal, Songlin Li & Jerome M. Siegel

  2. VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Ronald McGregor, Ming-Fung Wu, Thomas C. Thannickal, Songlin Li & Jerome M. Siegel

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  1. Ronald McGregor
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Contributions

R.M., M.-F.W., T.C.T. and J.M.S. designed the study. R.M. ran the anatomical experiments, M.-F.W. ran the behavioral experiments (wheel running and analgesia) and T.C.T. and S.L. ran the microglial studies. R.M., M.-F.W., T.C.T., S.L. and J.M.S. analyzed the results and R.M., M-F.W., T.C.T. and J.M.S. wrote the paper.

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Correspondence to Jerome M. Siegel.

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McGregor, R., Wu, MF., Thannickal, T.C. et al. Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing opioid analgesia. Nat. Mental Health 2, 1018–1031 (2024). https://doi.org/10.1038/s44220-024-00278-2

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