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A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence

Academic Article
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Overview

authors

  • Xu, H.
  • Partilla, J. S.
  • Wang, X. Y.
  • Rutherford, J. M.
  • Tidgewell, K.
  • Prisinzano, T. E.
  • Bohn, Laura
  • Rothman, R. B.

publication date

  • March 2007

journal

  • Synapse  Journal

abstract

  • Previous studies established that Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) and (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin) are fully efficacious mu-agonists. Herkinorin (HERK), unlike DAMGO, does not recruit beta-arrestin and promote mu-receptor internalization, even in cells that over express beta-arrestin. We hypothesized that chronic HERK and DAMGO treatment will differentially affect cellular markers of tolerance and dependence. CHO cells expressing the cloned human mu-receptor were treated for 20 h with 10 microM DAMGO, HERK, morphine, or medium. Both DAMGO and HERK acted as full agonists in the [(35)S]GTP-gamma-S binding assay with E(MAX) values of 230% and EC(50) values of 12.8 and 92.5 nM, respectively. In the cAMP assay, DAMGO and HERK had similar E(MAX) values of approximately 80% and EC(50) values of 3.23 and 48.7 nM, respectively. Chronic exposure to both drugs produced moderate tolerance to both drugs ( approximately 2 to 5 fold) in the [(35)S]GTP-gamma-S binding assay. In the cAMP assay, chronic DAMGO produced tolerance to both drugs ( approximately 3 to 4 fold). Chronic HERK eliminated the ability of either drug to inhibit forskolin-stimulated cAMP accumulation. Chronic DAMGO increased, and chronic HERK decreased, forskolin-stimulated cAMP accumulation. Naloxone, after chronic HERK (but not DAMGO) induced a large increase in forskolin-stimulated cAMP accumulation. Viewed collectively with published data, the current data indicate that both internalizing and noninternalizing mu-agonists produce cellular signs of tolerance and dependence.

subject areas

  • Analgesics, Opioid
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cell Membrane
  • Colforsin
  • Cricetinae
  • Cricetulus
  • Cyclic AMP
  • Drug Tolerance
  • Endocytosis
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Furans
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Humans
  • Narcotic Antagonists
  • Opioid-Related Disorders
  • Pyrones
  • Radioligand Assay
  • Receptors, Opioid, mu
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Research

keywords

  • DAMGO
  • G proteins
  • dependence
  • herkinorin
  • tolerance
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Identity

International Standard Serial Number (ISSN)

  • 0887-4476

Digital Object Identifier (DOI)

  • 10.1002/syn.20356

PubMed ID

  • 17152090
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Additional Document Info

start page

  • 166

end page

  • 175

volume

  • 61

issue

  • 3

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