Constitutive μ opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence

Z. Wang, E. J. Bilsky, Frank Porreca, W. Sadee

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

Chronic administration of narcotic μ opioid agonists results in tolerance and dependence. We propose that agonist stimulation causes a gradual conversion of μ receptors to a constitutively active state (μ*) as a key step in tolerance and physical dependence. We provide evidence in support of the existence of μ* in human neuroblastoma cells, SH-SY5Y, and μ* upregulation during morphine treatment. Naloxone blocked μ* activity, acting as an antagonist with negative intrinsic activity which accounts for its high potency in eliciting withdrawal. In contrast, the μ selective antagonist CTAP did not affect μ* activity but inhibited naloxone's effect. The protein kinase inhibitor H7 was found to suppress μ* formation, suggesting that μ* is phosphorylated. In a model of acute morphine tolerance/dependence in mice, H7 prevented naloxone induced withdrawal jumping and reversed morphine (antinociceptive) tolerance. CTAP caused only mild withdrawal and attenuated naloxone induced withdrawal, as predicted for an antagonist without negative activity. These results support a role for constitutive μ receptor activation in narcotic tolerance and dependence, affording potential separation of acute and chronic narcotic effects.

Original languageEnglish (US)
JournalLife Sciences
Volume54
Issue number20
StatePublished - 1994

Fingerprint

Opioid-Related Disorders
Narcotics
Opioid Receptors
Naloxone
Chemical activation
Morphine
Morphine Dependence
Protein Kinase Inhibitors
Neuroblastoma
Opioid Analgesics
Up-Regulation

Keywords

  • μ opioid receptor
  • activation
  • constitutive
  • dependence
  • tolerance

ASJC Scopus subject areas

  • Pharmacology

Cite this

Constitutive μ opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence. / Wang, Z.; Bilsky, E. J.; Porreca, Frank; Sadee, W.

In: Life Sciences, Vol. 54, No. 20, 1994.

Research output: Contribution to journalArticle

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