Chronic heroin self-administration desensitizes mu opioid receptor-activated G-proteins in specific regions of rat brain.
In previous studies from our laboratory, chronic noncontingent morphine administration decreased mu opioid receptor-activated G-proteins in specific brainstem nuclei. In the present study, mu 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). d(-1). mu opioid-stimulated [(35)S]GTPgammaS and [(3)H]naloxone autoradiography were performed in adjacent brain sections. Agonist-stimulated [(35)S]GTPgammaS autoradiography also examined other G-protein-coupled receptors, including delta opioid, ORL-1, GABA(B), adenosine A(1), cannabinoid, and 5-HT(1A). In brains from heroin self-administering rats, decreased mu opioid-stimulated [(35)S]GTPgammaS 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 mu opioid-stimulated [(35)S]GTPgammaS binding was found in thalamus and amygdala after heroin self-administration. Despite this decrease in mu-activated G-proteins, [(3)H]naloxone binding demonstrated increased mu opioid receptor binding in several brain regions after heroin self-administration, and there was a significant decrease in mu receptor G-protein efficiency as expressed as a ratio between agonist-activated G-proteins and mu receptor binding. No effects on agonist-stimulated [(35)S]GTPgammaS binding were found for any other receptor examined. The effect of chronic heroin self-administration to decrease mu-stimulated [(35)S]GTPgammaS 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.
Sim-Selley
L J
LJ
Department of Pharmacology and Toxicology, and Institute for Drug and Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Richmond, Virginia 23298, USA.
Selley
D E
DE
Vogt
L J
LJ
Childers
S R
SR
Martin
T J
TJ
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics*; D003932:Heroin / Q000008:administration & dosage* / Q000494:pharmacology; D006556:Heroin Dependence / Q000503:physiopathology*; D007700:Kinetics; D008297:Male; D009270:Naloxone / Q000493:pharmacokinetics; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D012646:Self Administration; D013462:Sulfur Radioisotopes; D014316:Tritium
D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D014316:Tritium; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003932:Heroin; D019204:GTP-Binding Proteins