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Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling

Nature Neuroscience volume 13, pages 284–286 (2010)Cite this article

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Abstract

To assess the importance of brain cytochrome P450 (P450) activity in μ opioid analgesic action, we generated a mutant mouse with brain neuron–specific reductions in P450 activity; these mice showed highly attenuated morphine antinociception compared with controls. Pharmacological inhibition of brain P450 arachidonate epoxygenases also blocked morphine antinociception in mice and rats. Our findings indicate that a neuronal P450 epoxygenase mediates the pain-relieving properties of morphine.

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Figure 1: Double immunolabeling showing expression of neuronal CPR in cerebral cortex (Ctx, top) and PAG (bottom) in control (WT, left) and null (right) mice.
Figure 2: Morphine antinociception in null and control mice.
Figure 3: Effects of P450 and epoxygenase inhibitors on morphine antinociception.

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Acknowledgements

The authors gratefully acknowledge the use of the Molecular Genetics and the Biochemistry Cores of the Wadsworth Center. We thank A. Verschoor for reading the manuscript, Y. Weng for assistance with chemical analysis, J. Phillips (Curragh Chemistries) for CC12 and A. Mongin for valuable discussions. This work was supported in part by US National Institutes of Health grants ES07462 (X.D.), DA03816 (L.B.H.), DA00360 (J.M.B.) and NS43466 (S.O.Z.).

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Author notes

  1. Jennie L Conroy and Cheng Fang: These authors contributed equally to this work.

  2. Xinxin Ding and Lindsay B Hough: These authors jointly directed the study.

Authors and Affiliations

  1. Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA

    Jennie L Conroy, Jun Yang, Melissa A VanAlstine, Julia W Nalwalk, Phillip J Albrecht, Joseph E Mazurkiewicz & Lindsay B Hough

  2. New York State Department of Health, Wadsworth Center, and School of Public Health, State University of New York at Albany, Albany, New York, USA

    Cheng Fang, Jun Gu, Weizhu Yang, Abigail Snyder-Keller, Melissa Behr & Xinxin Ding

  3. Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Scott O Zeitlin

  4. Integrated Tissue Dynamics, Rensselaer, New York, USA

    Phillip J Albrecht & Joseph E Mazurkiewicz

  5. Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, USA

    Zhixing Shan, Shao-Zhong Zhang & Mark P Wentland

  6. Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA

    Brian I Knapp & Jean M Bidlack

  7. Leiden/Amsterdam Center for Drug Research, VU University Amsterdam, Amsterdam, The Netherlands

    Obbe P Zuiderveld & Rob Leurs

Authors
  1. Jennie L Conroy
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  2. Cheng Fang
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  20. Xinxin Ding
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  21. Lindsay B Hough
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Contributions

J.L.C., J.W.N. and J.Y. performed all in vivo studies. C.F., J.G. and W.Y. contributed to the generation of the null mouse. C.F. performed most of the null mouse characterization, with additional help from J.G., M.B. and J.L.C. P.J.A., J.E.M. and A.S.-K. assisted with histochemistry and microscopy. M.A.V., J.L.C., B.I.K., J.M.B., O.P.Z. and R.L. performed drug, receptor and enzyme assays. Z.S., S.-Z.Z. and M.P.W. synthesized MW06-25. S.O.Z. provided the Camk2a-cre mouse. J.L.C., C.F., X.D. and L.B.H. wrote the manuscript. X.D. and L.B.H. supervised the overall design and performance of the project.

Corresponding authors

Correspondence to Xinxin Ding or Lindsay B Hough.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 2686 kb)

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Conroy, J., Fang, C., Gu, J. et al. Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling. Nat Neurosci 13, 284–286 (2010). https://doi.org/10.1038/nn.2497

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