Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration.
Previous studies have shown that chronic opiate treatment decreases mu opioid-stimulated [35S]GTPgammaS binding in specific brain regions. To extend these findings, the present study investigated DAMGO-stimulated [35S]GTPgammaS binding in membrane homogenates and coronal sections from rats non-contingently administered heroin. Rats were administered saline or increasing doses of heroin i.v. hourly up to 288 mg/kg/day over 40 days. In brain sections, chronic heroin administration decreased DAMGO-stimulated [35S]GTPgammaS binding in medial thalamus and amygdala, with no effect in cingulate cortex or nucleus accumbens. Chronic heroin administration also reduced [35S]GTPgammaS binding stimulated by the principal metabolite of heroin, 6-monoacetylmorphine. In contrast, no significant changes in mu opioid receptor binding were observed in amygdala or thalamus using [3H]DAMGO autoradiography. In membranes from amygdala and thalamus, chronic heroin treatment decreased the maximal effect of DAMGO in stimulating [35S]GTPgammaS binding, with no effect on DAMGO potency. GTPgammaS saturation analysis showed that chronic heroin treatment decreased the Bmax, and increased the K(D), of DAMGO-stimulated [35S]GTPgammaS binding. These data suggest potential mechanisms by which chronic agonist treatment produces opioid receptor/G-protein desensitization in brain.
Maher
Catherine E
CE
Department of Physiology and Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States.
Martin
Thomas J
TJ
Childers
Steven R
SR
D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009022:Morphine Derivatives / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D012646:Self Administration
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D009294:Narcotics; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003932:Heroin; D019204:GTP-Binding Proteins; C026979:6-O-monoacetylmorphine