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Rapid CommunicationShort Communication

Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

Lindsay B. Hough, Julia W. Nalwalk, Xinxin Ding and Nico Scheer
Drug Metabolism and Disposition September 2015, 43 (9) 1326-1330; DOI: https://doi.org/10.1124/dmd.115.065490
Lindsay B. Hough
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (L.B.H., J.W.N.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.); and Taconic Biosciences GmbH, Cologne, Germany (N.S.)
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Julia W. Nalwalk
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (L.B.H., J.W.N.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.); and Taconic Biosciences GmbH, Cologne, Germany (N.S.)
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Xinxin Ding
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (L.B.H., J.W.N.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.); and Taconic Biosciences GmbH, Cologne, Germany (N.S.)
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Nico Scheer
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (L.B.H., J.W.N.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.); and Taconic Biosciences GmbH, Cologne, Germany (N.S.)
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Abstract

Cytochrome P450 monooxygenases (P450s), which are well-known drug-metabolizing enzymes, are thought to play a signal transduction role in µ opioid analgesia and may serve as high-affinity 3H-cimetidine (3HCIM) binding sites in the brain. 3HCIM binding sites may also be related to opioid or nonopioid analgesia. However, of the more than 100 murine P450 enzymes, the specific isoform(s) responsible for either function have not been identified. Presently, three lines of constitutive P450 gene cluster knockout (KO) mice with full-length deletions of 14 Cyp2c, 9 Cyp2d, and 7 Cyp3a genes were studied for deficiencies in 3HCIM binding and for opioid analgesia. Liver and brain homogenates from all three genotypes showed normal 3HCIM binding values, indicating that gene products of Cyp2d, Cyp3a, and Cyp2c are not 3HCIM-binding proteins. Cyp2d KO and Cyp3a KO mice showed normal antinociceptive responses to a moderate systemic dose of morphine (20 mg/kg, s.c.), thereby excluding 16 P450 isoforms as mediators of opioid analgesia. In contrast, Cyp2c KO mice showed a 41% reduction in analgesic responses following systemically (s.c.) administered morphine. However, the significance of brain Cyp2c gene products in opioid analgesia is uncertain because little or no analgesic deficits were noted in Cyp2c KO mice following intracerebroventricular or intrathecalmorphine administration, respectively. These results show that the gene products of Cyp2d and Cyp3a do not contribute to µ opioid analgesia in the central nervous system. A possible role for Cyp2c gene products in opioid analgesia requires further consideration.

Footnotes

    • Received May 14, 2015.
    • Accepted June 24, 2015.
  • ↵1 Current affiliation: Independent Consultant, Cologne, Germany.

  • This work was supported by a grant from the National Institutes of Health National Institute on Drug Abuse [Grant DA027835].

  • dx.doi.org/10.1124/dmd.115.065490.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (9)
Drug Metabolism and Disposition
Vol. 43, Issue 9
1 Sep 2015
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Rapid CommunicationShort Communication

Opioid Analgesia in P450 Gene Cluster Knockout Mice

Lindsay B. Hough, Julia W. Nalwalk, Xinxin Ding and Nico Scheer
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1326-1330; DOI: https://doi.org/10.1124/dmd.115.065490

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Rapid CommunicationShort Communication

Opioid Analgesia in P450 Gene Cluster Knockout Mice

Lindsay B. Hough, Julia W. Nalwalk, Xinxin Ding and Nico Scheer
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1326-1330; DOI: https://doi.org/10.1124/dmd.115.065490
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