Tolerance to repeated morphine administration is associated with increased potency of opioid agonists

Susan L. Ingram, Tara A. Macey, Erin N. Fossum, Michael M. Morgan

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of μ-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize μ-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC50=281 nM) compared to saline (EC50=8.8 μM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the μ-opioid receptor antagonist β-funaltrexamine (β-FNA) suggesting that repeated morphine administration enhances agonist stimulation of μ-opioid receptor coupling to G-proteins. Although supersensitivity of μ-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of μ-opioid receptors.

Original languageEnglish (US)
Pages (from-to)2494-2504
Number of pages11
Issue number10
StatePublished - Sep 2008
Externally publishedYes


  • Antinociception
  • Descending pain pathway
  • Desensitization
  • GIRK channels
  • Periaqueductal gray
  • μ-opioid receptors

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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