Overexpression of Type 7 Adenylyl Cyclase in the Mouse Brain Enhances Acute and Chronic Actions of Morphine

  1. Masami Yoshimura1,
  2. Peter H. Wu1,
  3. Paula L. Hoffman and
  4. Boris Tabakoff
  1. Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado

    Abstract

    ABSTRACT

    The mechanisms by which morphine-induced analgesia and tolerance and physical dependence on morphine arise have been the subject of intense study, and much work has pointed to the involvement of cAMP-mediated events in the neuroadaptive phenomena leading to morphine tolerance and/or dependence. We overexpressed an opioid receptor-stimulatable form of adenylyl cyclase (type 7) in the central nervous system of mice and demonstrated significant effects of this manipulation on the animals' acute response to morphine, the development of morphine tolerance, and development of sensitization to morphine. Measurements of the acute analgesic response to morphine demonstrated that the ED50 values for the transgenic mice were significantly lower than the ED50 values determined for the “wild-type” animals. During chronic treatment with morphine, the transgenic mice developed tolerance more rapidly than the wild-type mice, and transgenic animals of the C57BL/6xSJL background showed a larger sensitization to morphine's effects on locomotor activity than did wild-type mice of the same background. These results indicated that cAMP-generating systems may simultaneously modulate the development of tolerance and sensitization. Interestingly, the signs of physical dependence on morphine in the transgenic mice did not differ from those in their wild-type litter mates, indicating that separate mechanisms may modulate opiate tolerance and opiate dependence.

    Footnotes

    • Send reprint requests to: Boris Tabakoff, Ph.D., Department of Pharmacology, University of Colorado School of Medicine, 4200 East Ninth Avenue, C236, Denver, CO 80262. E-mail: boris.tabakoff{at}uchsc.edu

    • ↵1 These authors contributed equally to the work.

    • This work was supported by funds from the Banbury Foundation and the National Institute on Alcohol Abuse and Alcoholism (AA9014, AA3527, and AA00240).

    • Abbreviations:
      AC
      adenylyl cyclase
      AC7
      type VII adenylyl cyclase
      TG
      transgenic
      WT
      wild type
      DAMGO
      [d-Ala2,N-MePhe4,Gly-o15]enkephalin
      CREB
      cAMP response element-binding protein
      VIP
      vasoactive intestinal peptide
      CNS
      central nervous system
      • Received February 7, 2000.
      • Accepted July 24, 2000.
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    1. Molecular Pharmacology November 1, 2000 vol. 58 no. 5 1011-1016
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