Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats

Ahmad A. Altarifi, Laurence L. Miller, S. Stevens Negus

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The net effect of μ-opioid receptor agonists on intracranial self-stimulation (ICSS) in rats reflects an integration of rate-increasing and rate-decreasing effects. Previous opioid exposure is associated with tolerance to rate-decreasing effects and the augmented expression of abuse-related rate-increasing effects. This finding was replicated here with morphine. Subsequent studies then tested the hypothesis that opioid agonist-induced rate-decreasing effects require the activation of a larger relative fraction of μ receptors, and hence are more vulnerable to tolerance-associated reductions in receptor density than rate-increasing effects. Two sets of experiments were conducted to test this hypothesis. First, the effects of morphine on ICSS were examined after pretreatment with the irreversible μ antagonist β-funaltrexamine to reduce the density of available μ receptors. Second, effects were examined for a range of μ opioids that varied in relative efficacy at μ receptors. The hypothesis predicted that (a) morphine, after β-funaltrexamine treatment, or (b) low-efficacy μ agonists would mimic the effects of morphine tolerance to produce the reduced expression of rate-decreasing effects and enhanced expression of rate-increasing effects. Neither of these predictions were supported. These results indicate that μ agonist-induced facilitation and depression of ICSS may be mediated by distinct populations of μ receptors that respond differently to regimens of opioid exposure.

Original languageEnglish (US)
Pages (from-to)678-692
Number of pages15
JournalBehavioural pharmacology
Volume23
Issue number7
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

Keywords

  • drug abuse
  • efficacy
  • intracranial self-stimulation
  • morphine
  • opioid
  • rat

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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