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 adm inistration decreased mu opioid receptor-activated G-proteins in specific b rainstem nuclei. In the present study, m opioid receptor binding and recept or-activated G-proteins were examined after chronic heroin self-administrat ion. 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-stimulat ed [S-35]GTP gamma S and [H-3]naloxone autoradiography were performed in ad jacent brain sections. Agonist-stimulated [S-35]GTP gamma S autoradiography also examined other G-protein-coupled receptors, including delta opioid, O RL-1, GABA(B), adenosine A(1), cannabinoid, and 5-HT1A. In brains from hero in self-administering rats, decreased mu opioid-stimulated [S-35]GTP gamma S binding was observed in periaqueductal gray, locus coeruleus, lateral par abrachial nucleus, and commissural nucleus tractus solitarius, as previousl y observed in chronic morphine-treated animals. In addition, decreased mu o pioid-stimulated [S-35]GTP gamma S binding was found in thalamus and amygda la after heroin self-administration. Despite this decrease in mu-activated G-proteins, [H-3]naloxone binding demonstrated increased mu opioid receptor binding in several brain regions after heroin self-administration, and the re was a significant decrease in m receptor G-protein efficiency as express ed as a ratio between agonist-activated G-proteins and m receptor binding. No effects on agonist-stimulated [S-35]GTP gamma S binding were found for a ny other receptor examined. The effect of chronic heroin self-administratio n to decrease mu-stimulated [S-35]GTP gamma S binding varied between region s 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 chron ic effects of opioids develop to different degrees.