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

21 Citations (Scopus)

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

Fingerprint

Self Stimulation
Opioid Receptors
Morphine
Opioid Analgesics
Population

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats. / Altarifi, Ahmad A.; Miller, Laurence L; Stevens Negus, S.

In: Behavioural Pharmacology, Vol. 23, No. 7, 01.10.2012, p. 678-692.

Research output: Contribution to journalArticle

@article{1ebf9dd51cf947109155fa81de53debc,
title = "Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats",
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.",
keywords = "drug abuse, efficacy, intracranial self-stimulation, morphine, opioid, rat",
author = "Altarifi, {Ahmad A.} and Miller, {Laurence L} and {Stevens Negus}, S.",
year = "2012",
month = "10",
day = "1",
doi = "10.1097/FBP.0b013e328358593c",
language = "English (US)",
volume = "23",
pages = "678--692",
journal = "Behavioural Pharmacology",
issn = "0955-8810",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats

AU - Altarifi, Ahmad A.

AU - Miller, Laurence L

AU - Stevens Negus, S.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

KW - drug abuse

KW - efficacy

KW - intracranial self-stimulation

KW - morphine

KW - opioid

KW - rat

UR - http://www.scopus.com/inward/record.url?scp=84866321680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866321680&partnerID=8YFLogxK

U2 - 10.1097/FBP.0b013e328358593c

DO - 10.1097/FBP.0b013e328358593c

M3 - Article

VL - 23

SP - 678

EP - 692

JO - Behavioural Pharmacology

JF - Behavioural Pharmacology

SN - 0955-8810

IS - 7

ER -