EFFECTS OF CHRONIC MORPHINE ADMINISTRATION ON MU-OPIOID RECEPTOR-STIMULATED [S-35] GTP-GAMMA-S AUTORADIOGRAPHY IN RAT-BRAIN

Chronic opiate administration results in the development of tolerance and dependence, but the regulation of mu opioid receptor function duri ng this process is not clearly understood. To localize changes in mu o pioid receptor-coupled G-protein activity in various brain regions aft er chronic morphine treatment, the present study examined mu opioid ag onist-stimulated [S-35]GTP gamma S binding to brain sections by in vit ro autoradiography. Rats were treated for 12 d with increasing doses ( 10-320 mg . kg(-1) . d(-1)) of morphine. Control rats were injected wi th either saline or a single acute injection of morphine (20 mg/kg). m u opioid-stimulated [S-35]GTP gamma S binding was measured by autoradi ography of brain sections in the presence and absence of the mu opioid -selective agonist DAMGO. In rats injected with a single acute dose of morphine, no significant changes were detected in basal or agonist-st imulated [S-35]GTP gamma S binding in any region. In sections from chr onic morphine-treated rats, however, DAMGO-stimulated [S-35]GTP gamma S binding was reduced significantly compared with control rats in the following brainstem nuclei: dorsal raphe nucleus, locus coeruleus, lat eral and medial parabrachial nuclei, and commissural nucleus tractus s olitarius. No significant changes were observed in several other brain regions, including the nucleus accumbens, amygdala, thalamus, and sub stantia nigra. These data indicate that chronic morphine administratio n results in reductions in mu opioid activation of G-proteins in speci fic brainstem nuclei involved in physiological homeostasis and autonom ic function, which may have implications in the development of opiate tolerance and physical dependence.