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The Journal of Neuroscience, June 15, 2000, 20(12):4555-4562
Chronic Heroin Self-Administration Desensitizes µ Opioid
Receptor-Activated G-Proteins in Specific Regions of Rat Brain
Laura J.
Sim-Selley1,
Dana E.
Selley1,
Leslie J.
Vogt2,
Steven R.
Childers2, and
Thomas J.
Martin2
1 Department of Pharmacology and Toxicology, and
Institute for Drug and Alcohol Studies, Virginia Commonwealth
University Medical College of Virginia, Richmond, Virginia 23298, and
2 Department of Physiology/Pharmacology, and Center for the
Neurobiological Investigation of Drug Abuse, Wake Forest University
School of Medicine, Winston-Salem, North Carolina 27157
In previous studies from our laboratory, chronic noncontingent
morphine administration decreased µ opioid receptor-activated G-proteins in specific brainstem nuclei. In the present study, µ opioid receptor binding and receptor-activated G-proteins were examined
after chronic heroin self-administration. Rats were trained to
self-administer intravenous heroin for up to 39 d, achieving heroin intake up to 366 mg · kg 1 · d1. µ opioid-stimulated [35S]GTP S and
[3H]naloxone autoradiography were performed in
adjacent brain sections. Agonist-stimulated
[35S]GTPS autoradiography also examined other
G-protein-coupled receptors, including  opioid, ORL-1,
GABAB, adenosine A1, cannabinoid, and 5-HT1A. In brains from heroin self-administering rats,
decreased µ opioid-stimulated [35S]GTPS
binding was observed in periaqueductal gray, locus coeruleus, lateral
parabrachial nucleus, and commissural nucleus tractus solitarius, as
previously observed in chronic morphine-treated animals. In addition,
decreased µ opioid-stimulated [35S]GTPS
binding was found in thalamus and amygdala after heroin self-administration. Despite this decrease in µ-activated G-proteins, [3H]naloxone binding demonstrated increased µ opioid receptor binding in several brain regions after
heroin self-administration, and there was a significant decrease in µ receptor G-protein efficiency as expressed as a ratio between
agonist-activated G-proteins and µ receptor binding. No effects on
agonist-stimulated [35S]GTPS binding were found
for any other receptor examined. The effect of chronic heroin
self-administration to decrease µ-stimulated [35S]GTPS binding varied between regions and
was highest in brainstem and lowest in the cortex and striatum. These
results not only provide potential neuronal mechanisms that may
contribute to opioid tolerance and dependence, but also may explain why
various chronic effects of opioids develop to different degrees.
Key words:
µ opioid receptor; heroin; G-protein; desensitization; opioid receptor; nociceptin/orphanin FQ receptor
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124555-08$05.00/0
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