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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Opioid peptide receptor studies. 16. Chronic morphine alters G-protein function in cells expressing the cloned mu

Heng Xu1, Yi-Feng Lu, Richard B Rothman

  • 1Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.

Synapse (New York, N.Y.)
|November 8, 2002
PubMed

Insights

Chronic morphine treatment causes functional uncoupling of mu opioid receptors and G proteins, impacting signaling pathways. This study reveals molecular changes underlying morphine tolerance in human mu opioid receptor-expressing cells.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • Chronic morphine treatment leads to functional uncoupling of mu opioid receptors (MOR) and G proteins.
  • This uncoupling affects cellular signaling pathways involved in pain perception and tolerance.
  • Understanding these molecular mechanisms is crucial for developing effective pain management strategies.

Purpose of the Study:

  • To investigate the molecular changes in MOR-G protein coupling following chronic morphine treatment.
  • To characterize the alterations in G protein activation and downstream signaling in response to morphine.
  • To determine if these changes are linked to the development of morphine tolerance.

Main Methods:

  • Utilized Chinese hamster ovary (CHO) cells stably expressing the human mu opioid receptor (hMOR-CHO cells).
  • Cells were incubated with morphine to induce chronic treatment, followed by assessment of DAMGO- and morphine-stimulated [(35)S]-GTP-gamma-S binding.
  • Agonist-mediated inhibition of forskolin-stimulated cAMP accumulation was measured to assess G protein signaling.

Main Results:

  • Chronic morphine treatment shifted the EC(50) for morphine and DAMGO, indicating reduced receptor sensitivity.
  • Maximal G protein stimulation (E(max)) was decreased, suggesting impaired receptor-G protein coupling.
  • Analysis revealed changes in high-affinity G protein binding sites, with morphine altering K(d) but not B(max) in treated cells.
  • A significant increase in EC(50) was observed for agonist-mediated inhibition of cAMP accumulation.

Conclusions:

  • Chronic morphine treatment induces functional changes in MOR-G protein coupling, characterized by reduced signaling efficacy.
  • These molecular alterations are associated with the development of morphine tolerance.
  • The observed changes were specific to functional MOR and did not occur in a mutant receptor lacking tolerance development, confirming their link to morphine tolerance.

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