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Retention of heroin and morphine–6β–glucuronide analgesia in a new line of mice lacking exon 1 of MOR–1

Nature Neuroscience volume 2, pages 151–156 (1999)Cite this article

Abstract

Morphine produces analgesia by activating mu opioid receptors encoded by the MOR–1 gene. Although morphine–6β–glucuronide (M6G), heroin and 6–acetylmorphine also are considered mu opioids, recent evidence suggests that they act through a distinct receptor mechanism. We examined this question in knockout mice containing disruptions of either the first or second coding exon of MOR–1. Mice homozygous for either MOR–1 mutation were insensitive to morphine. Heroin, 6–acetylmorphine and M6G still elicited analgesia in the exon–1 MOR–1 mutant, which also showed specific M6G binding, whereas M6G and 6–acetylmorphine were inactive in the exon–2 MOR–1 mutant. These results provide genetic evidence for a unique receptor site for M6G and heroin analgesia.

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Figure 1: Creation of MOR–1 exon–1 mutant mice.
Figure 2: Analgesic action of opioids in wild–type, heterozygous or homozygous mice.
Figure 3: Inhibition of M6G analgesia by selective opioid receptor antagonists.
Figure 4: Antisense effects of M6G analgesia.
Figure 5: [3H]M6G binding in exon–1 MOR–1 mutant mice.
Figure 6: RT–PCR of MOR–1 transcripts in exon–1–deficient mice.

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Acknowledgements

The authors thank Rhuna Shen and Qian Ye for their contributions in mapping the mu opioid receptor gene and constructing the targeting vector. We thank Chris Evans, Jim Douglass and Grahaem Bell for providing probes for DOR–1, proenkephalin/prodynorphin and KOR–1, respectively, Z.P. Chen for providing the mouse ORL in situ probe, and Liz Robertson for providing CCE ES cells. We also thank Brigitte Kieffer and Hans Matthes for providing the exon–2 MOR–1 mutant mice. This work was supported by grants from the National Institute on Drug Abuse to J.E.P. (DA–09040 and DA–08622), Y.–X.P. (DA–00296) and G.W.P. (DA–07241, DA–02615 and a Research Scientist Award DA–00220) and a core grant from the National Cancer Institute to Memorial Sloan–Kettering Cancer Center (CA–08748). D.J.M. was supported by NIH training grant R25–GM–55145.

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Author notes

  1. Ellen M. Unterwald

    Present address: Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, Pennsylvania, 19140, USA

  2. Ellen M. Unterwald

    Present address: The Rockefeller University, 1230 York Avenue, New York, New York, 10021, USA

Authors and Affiliations

  1. Dept. of Neuroscience and Cell Biology, UMDNJ–Robert Wood Johnson Medical School, CABM, RM 326, 675 Hoes Lane, Piscataway, 08854, New Jersey, USA

    Alwin G.P. Schuller, Jiwen Zhang, Daniel J. Morgan, Maureen E. Czick & John E. Pintar

  2. The Cotzias Laboratory of Neuro–Oncology, Memorial Sloan–Kettering Cancer Center, 125 York Avenue, New York, 10021, New York, USA

    Michael A. King, Elizabeth Bolan, Ying–Xian Pan, Albert Chang & Gavril W. Pasternak

  3. Dept. of Psychiatry, NYU Medical Center, 550 First Avenue, New York, 10016, New York, USA

    Ellen M. Unterwald

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Correspondence to John E. Pintar.

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Schuller, A., King, M., Zhang, J. et al. Retention of heroin and morphine–6β–glucuronide analgesia in a new line of mice lacking exon 1 of MOR–1. Nat Neurosci 2, 151–156 (1999). https://doi.org/10.1038/5706

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