UP-regulation of NO-cGMP signal transduction system is involved in the biological mechanisms of opiate tolerance and withdrawal

Meng Wei Zang, Ai Min Meng, Qi Shen, Qing Wang, Fei Guo, Jing Sheng Liu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


AIM: To determine the effect of chronic treatment with opioid agonists on NO-cGMP signal system on the basis of successful establishment of a NG-LNCXiNOS cell line expressing iNOS cDNA and a cell model of opioid tolerance and naloxone-precipitated withdrawal. METHODS: NOS activity and cGMP content were determined by the conversion of 3H-Arginine to 3H-Citrulline and radioimmunoassay, respectively. Western blot analysis and NADPH diaphorase (NADPH-d) histochemical assay were used to detecte the level of iNOS gene expression and NADPH-d activity which is a histochemical marker for NOS. RESULTS: Long-term exposure of NG-LNCXiNOS cells to various opioid agonists enhanced the cytosolic iNOS activity, accompanying the increase in intracellular cGMP content in a dose-dependent manner. The order of potencies was DPDPE〉 DADLE〉 morphine. The EC50 values of the above indicators were nmol·L-1 level. When naloxone induced cell withdrawal, the iNOS activity and cGMP level were dramatically higher than those with agonists alone. Pretreatment of the cells with the more efficacious δ-ligand (DPDPE) for 48 hours also may lead to high-level expression of iNOS protein and elevate the number of NADPH diaphorase-positive cells. CONCLUSION: Chronic opioid treatment was shown to up-regulate the NO-cGMP signal pathway, which may reflect an important biochemical change accounting for development of tolerance to and dependence on opiate. Thus, NGLNCXiNOS cells provide a suitable system for studying the relationship between AC-cAMP and NO-cGMP signal system on the molecular mechanisms of opiate tolerance and dependence.

Original languageEnglish (US)
Pages (from-to)566-570
Number of pages5
JournalYaoxue Xuebao
Issue number8
StatePublished - Aug 1 2000
Externally publishedYes


  • Cyclic GMP
  • Nitric-oxide synthase
  • Opiate dependence
  • Signal transduction
  • δ-opioid receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)


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