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Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling


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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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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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.

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Correspondence to Xinxin Ding or Lindsay B Hough.

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The authors declare no competing financial interests.

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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).

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