Overexpression of Dynamin Is Induced by Chronic Stimulation of μ- but Not δ-Opioid Receptors: Relationships with μ-Related Morphine Dependence

  1. Florence Noble1,
  2. Maria Szücs2,
  3. Brigitte Kieffer3 and
  4. Bernard P. Roques1
  1. 1Département de Pharmacochimie Moléculaire et Structurale, Institut National de la Santé et de la Recherche Médicale U266, Centre National de la Recherche Scientifique UMR8600, Université René Descartes, Unité de Formation et de Recherche des Sciences Pharmaceutiques et Biologiques, Paris, France (F.N., B.P.R.); 2Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary (M.S.); and 3Laboratoire des Récepteurs et Protéines Membranaires, Centre National de la Recherche Scientifique UPR 9050, Université Strasbourg 1, ESBS Pole API, Illkirch, France (B.K.)

    Abstract

    Several studies using selective opioid agonists or mice with a deletion of the μ-opioid receptor, have shown that morphine dependence is essentially due to chronic stimulation of μ- but not δ-opioid receptors. Because dependence is assumed to be related to persistent intracellular modifications, we have investigated modifications putatively induced by chronic activation of μ receptors with morphine or selective agonists in vitro in SH-SY5Y cells and in vivo in different strains of mice, including mice lacking the μ-opioid receptor gene. The results show a similar down-regulation and desensitization of μ and δ binding sites, whereas an overexpression of dynamin occurred only with μ agonists, strongly suggesting the relevance of this up-regulation with the opiate dependence. Moreover, translocation of overexpressed dynamin from intracellular pools to plasma membranes was observed in chronic morphine-treated rats. This recruitment could be critically involved in long-lasting changes such as alterations of axonal transport observed in opioid dependence.

    Footnotes

    • Professor B. P. Roques, Institut National de la Santé et de la Recherche Médicale U266, Centre National de la Recherche Scientifique UMR 8600, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France. E-mail:roques{at}pharmacie.univ-paris5.fr

    • This work was supported by institutional grants from Centre National de la Recherche Scientifique and INSERM (France), grants from the European Community (BMH4 CT98 2267), and research grants OTKA T-16084, TÉT JFNo. 564. A short travel fund was provided by the French Embassy (Service Culturel, Scientifique et de Coopération) to M. Szücs.

    • Abbreviations:
      DAMGO
      H-Tyr-d-Ala-Gly-N-Me-Phe-glycinol
      SNC 80
      (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
      BUBU
      Tyr-d-Ser-(O-tertiobutyl)Gly-Phe-Leu-Thr(O-tertiobutyl)
      DPDPE
      Tyr-d-Pen-Gly-Phe-d-Pen
      PAGE
      polyacrylamide gel electrophoresis
      SPM
      synaptic plasma membranes
      MI
      microsomes
      MAP
      mitogen-activated protein
      • Received December 3, 1999.
      • Accepted March 13, 2000.
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    1. Molecular Pharmacology July 1, 2000 vol. 58 no. 1 159-166
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