Changes in [ 3 H]‐UK14304 binding to α 2 ‐adrenoceptors in morphine‐dependent guinea‐pigs

1 The aim of this study was to investigate the effect of a noradrenergic input in the cortex of morphine‐dependent animals. Binding of the α 1 ‐adrenoceptor ligand [ 3 H]‐prazosin did not change in cortical membranes taken from morphine‐dependent as compared to control guinea‐pigs. However, binding of the α 2 ‐adrenoceptor ligand [ 3 H]‐UK14304 showed decreased K D (−30%) in the absence of significant changes in B max , either in cortical membranes or in synaptosomes. 2 Several characteristics of this phenomenon were identified. First, it occurs in a time‐dependent fashion, in that it takes 5 days of chronic morphine treatment to start developing. Second, it can be observed after acute administration of high doses of morphine (100 mg kg −1 ). Third, it does not require a connection with the locus coeruleus or with other subcortical structures, in that it can be reproduced in vitro in isolated cortical slices. Fourth, it requires the integrity of cortical structures, since it cannot be reproduced in vitro in cortical synaptosomes. 3 Release studies were run to attempt identification of a functional correlate of the above observations. No changes were observed in the ability of the α 2 ‐adrenoceptor agonist UK14304 to inhibit 35 mM K + ‐ evoked [ 3 H]‐noradrenaline outflow from cortical synaptosomes taken from morphine‐dependent as compared to control guinea‐pigs. However, a large decrease in the IC 50 of UK14304 for the inhibition of 35 mM K + ‐evoked [ 3 H]‐γ‐aminobutyric acid ([ 3 H]‐GABA) outflow (41 vs. 501 nM) was observed in morphine‐dependent as compared to control animals. 4 These data suggest that, in the guinea‐pig, chronic morphine treatment is associated with a shift from a low to high affinity agonist state in α 2 ‐adrenoceptors on cortical GABA terminals.