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Journal of Pharmacology and Experimental Therapeutics

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OtherNEUROPHARMACOLOGY

3H-Morphine-6β-Glucuronide Binding in Brain Membranes and an MOR-1-Transfected Cell Line

George P. Brown, Ke Yang, Ouathek Ouerfelli, Kelly M. Standifer, David Byrd and Gavril W. Pasternak
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1291-1297;
George P. Brown
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Ke Yang
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Ouathek Ouerfelli
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Kelly M. Standifer
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David Byrd
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Gavril W. Pasternak
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Abstract

Morphine-6β-glucuronide (M6G) is a potent morphine metabolite. In an effort to further explore its mechanisms of action, we synthesized3H-M6G of high specific activity and examined its binding. Although its affinity toward traditional mureceptors is similar to morphine in binding assays in brain and in Chinese hamster ovary cells stably transfected with MOR-1, M6G is >100-fold more potent than morphine in analgesic assays. This apparent discrepancy cannot be explained by differing intrinsic activities of the two drugs because both agents are partial agonists with similar efficacies in adenylyl cyclase assays in the transfected cell lines. Behavioral studies have implied the possibility of a distinct M6G receptor. Detailed binding studies in brain tissue reveal evidence for heterogeneity. Nonlinear regression analysis of3H-M6G saturation studies reveals two components. The lower-affinity component (KD = 1.93 ± 0.6 nM) corresponds to labeling of traditionalmu receptors. In addition, 3H-M6G labels another site of low abundance with very high affinity (KD = 68 ± 7 pM). Competition studies indicate that both sites are relatively muselective. However, several compounds clearly distinguish between the two sites. These binding studies support the concept of a unique M6G receptor responsible for its analgesic activity.

Footnotes

  • Send reprint requests to: Dr. Gavril W. Pasternak, Department of Neurology, 1275 York Avenue, New York, NY 10021. E-mail:pasterng{at}mskmail.mskcc.org

  • ↵1 This work was supported in part by Grant DA06241 and Research Scientist Award K05-DA00220 from the National Institute on Drug Abuse (G.W.P.). G.P.B. and K.Y. were supported by National Institute on Drug Abuse Training Grant T32-DA07274. This work also was supported by Core Grant CA08748 from the National Cancer Institute.

  • Abbreviations:
    TAPP
    Tyr-d-Ala-Phe-Phe-NH2
    PL-017
    Tyr-Pro-N-Me-Phe-d-Pro-NH2
    M6G
    morphine-6β-glucuronide
    DADLE
    [d-Ala2,d-Leu5]enkephalin
    DAMGO
    [d-Ala2,Me-Phe4,Gly(ol)5]enkephalin
    CHO
    Chinese hamster ovary
    PBS
    phosphate-buffered saline
    • Received December 30, 1996.
    • Accepted May 16, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherNEUROPHARMACOLOGY

3H-Morphine-6β-Glucuronide Binding in Brain Membranes and an MOR-1-Transfected Cell Line

George P. Brown, Ke Yang, Ouathek Ouerfelli, Kelly M. Standifer, David Byrd and Gavril W. Pasternak
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1291-1297;

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OtherNEUROPHARMACOLOGY

3H-Morphine-6β-Glucuronide Binding in Brain Membranes and an MOR-1-Transfected Cell Line

George P. Brown, Ke Yang, Ouathek Ouerfelli, Kelly M. Standifer, David Byrd and Gavril W. Pasternak
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1291-1297;
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