Effect of opioid antagonists on acetylcholine release from Guinea-pig brain slices: Influence of peptidase inhibition

Abstract

With the aim of ascertaining the existence of an endogenous opioid control on cholinergic structures, the effects of the opioid antagonists naloxone, Mr 1452, Mr 2266, and ICI 174864 on spontaneous and electrically evoked [ 3H]choline (Ch) efflux from guinea-pig brain slices were tested. In cerebral cortex and caudate nucleus slices, no drug changed either resting or stimulus-evoked 3H-Ch efflux whether in the absence or in the presence of peptidase inhibitors (thiorphan 0·3 μM, bestatin 10μm, captopril 10 μm, l-leucyl- l-leucine 2 m m). Conversely, in thalamus slices, the benzomorphan opioid antagonists Mr 1452 and Mr 2266 (but not their non-opioid stereoisomers Mr 1453 and Mr 2267) dose dependently increased St 2/St 1 ratios, when applied 15 min before St 2 to slices superfused with normal Krebs solution. Peptidase inhibition potentiated the facilitatory effect of Mr compounds. Peptidase inhibitors per se reduced the stimulus evoked efflux of 3H-Ch, when present either from the beginning or from 15 min before St, and potentiated the inhibition induced by dynorphin (1–13) (Dyn). Mr 2266 fully antagonized any inhibitory effect induced by peptidase inhibitors, Dyn or their combination. ICI 174864, a selective δ antagonist, did not affect 3H-Ch efflux, while naloxone showed a tendency to increase it when peptidases were inhibited. Taken together, these data suggest the existence of an endogenous opioid tone inhibiting acetylcholine release in the guinea-pig thalamus. The relative affinities of the antagonists used suggest that the receptor involved may be of the K type.