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Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

Nature Medicine volume 23, pages 164–173 (2017)Cite this article

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Abstract

Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.

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Figure 1: MORs are required for morphine antinociceptive tolerance and OIH, but are not expressed by spinal microglia.
Figure 2: Conditional deletion of MORs from primary afferent nociceptors does not alter nociceptive behavior or reduce systemic morphine antinociception.
Figure 3: Conditional deletion of MORs from TRPV1 nociceptors prevents the onset of morphine antinociceptive tolerance and OIH.
Figure 4: Opioid-induced spinal LTP is initiated by presynaptic MORs in nociceptors.
Figure 5: Pharmacological blockade of peripheral MORs by MNB dose dependently prevents the onset of morphine antinociceptive tolerance and OIH.
Figure 6: Combination therapy of morphine and MNB delivers long-lasting antinociception, without the onset of tolerance, during perioperative and chronic pain states.

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Acknowledgements

We thank B. Kieffer (McGill University) for providing the Oprm1 floxed mice and MOR-mCherry mice, C. Evans (University of California, Los Angeles) and F. Simonin (Université de Strasbourg) for providing critical immunohistochemical and pharmacological reagents, J. Kaslow and A. Yu-Chun Wong for assistance with data analysis, and H. Nguyen (Stanford University) for assistance with illustration design. This work was supported by US National Institutes of Health (NIH) grant DA031777 (G.S.), the Rita Allen Foundation and American Pain Society Award in Pain (G.S.), NIH Fellowships F32DA041029 (G.C.), T32GM089626 (D.W.), and T32DA35165 (G.C.), Foundation for Anesthesia Education and Research (FAER) Mentored Research Training grant (V.L.T.), DoD National Defense Science and Engineering Graduate (NDSEG) Fellowship (E.I.S.), NSF Graduate Research Fellowship and Stanford Bio-X Graduate Fellowship (J.R.D.), NIH grant R37DA15043 (B.A.B.), and Damon Runyon Cancer Research Foundation postdoctoral fellowship (C.J.B.).

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  1. Gregory Corder, Vivianne L Tawfik, Dong Wang and Elizabeth I Sypek: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA

    Gregory Corder, Vivianne L Tawfik, Dong Wang, Elizabeth I Sypek, Sarah A Low, Jasmine R Dickinson, Chaudy Sotoudeh, J David Clark & Grégory Scherrer

  2. Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, USA

    Gregory Corder, Vivianne L Tawfik, Dong Wang, Sarah A Low, Chaudy Sotoudeh & Grégory Scherrer

  3. Department of Neurosurgery, Stanford University, Stanford, California, USA

    Gregory Corder, Vivianne L Tawfik, Dong Wang, Sarah A Low, Chaudy Sotoudeh & Grégory Scherrer

  4. Stanford Neurosciences Institute, Stanford, California, USA

    Gregory Corder, Vivianne L Tawfik, Dong Wang, Sarah A Low, Chaudy Sotoudeh, Ben A Barres, Christopher J Bohlen & Grégory Scherrer

  5. Stanford University Neuroscience Graduate Program, Stanford, California, USA

    Elizabeth I Sypek

  6. Stanford University Biology Graduate Program, Stanford, California, USA

    Jasmine R Dickinson

  7. Anesthesiology Service, Veteran's Affairs Palo Alto Health Care System, Palo Alto, California, USA

    J David Clark

  8. Department of Neurobiology, Stanford University, Stanford, California, USA

    Ben A Barres & Christopher J Bohlen

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Contributions

G.C. and J.R.D. performed behavioral pharmacology. G.C., V.L.T., D.W., E.I.S., S.A.L. and C.S. performed histology. D.W. performed spinal cord slice electrophysiology. E.I.S., C.J.B. and B.A.B. designed and performed RNA transcriptome sequencing. J.D.C. provided critical input on study design and interpretation. G.C., V.L.T., D.W., E.I.S., J.R.D. and G.S. designed studies and wrote the manuscript. G.S., G.C., V.L.T. and D.W. conceived the project, and G.S. supervised all experiments. All of the authors contributed to data analysis, interpretation and editing of the manuscript.

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Correspondence to Grégory Scherrer.

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Corder, G., Tawfik, V., Wang, D. et al. Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med 23, 164–173 (2017). https://doi.org/10.1038/nm.4262

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