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

Authors :
Laurence Miller
Ahmad A. Altarifi
S. Stevens Negus
Source :
Behavioural Pharmacology. 23:678-692
Publication Year :
2012
Publisher :
Ovid Technologies (Wolters Kluwer Health), 2012.

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.

Details

ISSN :
09558810
Volume :
23
Database :
OpenAIRE
Journal :
Behavioural Pharmacology
Accession number :
edsair.doi.dedup.....79994cce5f8af9e39959de77461b4375
Full Text :
https://doi.org/10.1097/fbp.0b013e328358593c