CHANGES IN [H-3] UK14304 BINDING TO ALPHA(2)-ADRENOCEPTORS IN MORPHINE-DEPENDENT GUINEA-PIGS

1 The aim of this study was to investigate the effect of a noradrenerg ic;input in the cortex of morphine-dependent animals. Binding of the a lpha(1)-adrenoceptor ligand [H-3]-prazosin did not change in cortical membranes taken from morphine-dependent as compared to control guinea- pigs. However, binding of the alpha(2)-adrenoceptor ligand [H-3]-UK143 04 showed decreased K-D (-30%) in the absence of significant changes i n B-max either in cortical membranes or in synaptosomes. 2 Several cha racteristics of this phenomenon were identified. First, it occurs in a time-dependent fashion, in that it takes 5 days of chronic morphine t reatment to start developing. Second, it can be observed after acute a dministration of high doses of morphine (100 mg kg(-1)). Third, it doe s not require a connection with the locus coeruleus or with other subc ortical structures, in that it can be reproduced in vitro in isolated cortical slices. Fourth, it requires the integrity of cortical structu res, since it cannot be reproduced in vitro in cortical synaptosomes. 3 Release studies were run to attempt identification of a functional c orrelate of the above observations. No changes were observed in the ab ility of the alpha(2)-adrenoceptor agonist UK14304 to inhibit 35 mM K-evoked [H-3]-noradrenaline outflow from cortical synaptosomes taken f rom morphine-dependent as compared to control guinea-pigs. However, a large decrease in the IC50 of UK14304 for the inhibition of 35 mM K+-e voked [H-3]-gamma-aminobutyric acid ([H-3]-GABA) outflow (41 vs. 501 n M) was observed in morphine-dependent as compared to control animals. 4 These data suggest that, in the guinea-pig, chronic morphine treatme nt is associated with a shift from a low to high affinity agonist stat e in az-adrenoceptors on cortical GABA terminals.