Deletion of guanine nucleotide binding protein αz subunit in mice induces a gene dose dependent tolerance to morphine

K. J. Leck, S. E. Bartlett, M. T. Smith, D. Megirian, J. Holgate, K. L. Powell, K. I. Matthaei, I. A. Hendry

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12 Citations (Scopus)


The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G z, a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the Gz second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Gαz knockout mouse develops significantly increased tolerance to morphine, which depends on Gαz gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that Gz signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.

Original languageEnglish
Pages (from-to)836-846
Number of pages11
Issue number6
Publication statusPublished - May 2004
Externally publishedYes


  • %MPE, percentage of maximum possible effect
  • Analgesia
  • ANOVA, analysis of variance
  • DAMGO, [d-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin
  • DPDPE, [d-Pen2,d-Pen5]-enkephalin
  • G protein
  • G protein, guanine nucleotide binding protein
  • Gz
  • Lethality
  • Opioid

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