Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals

We investigated the effects of salvinorin A on the basal and the 12 mM K+-evoked release of preloaded [3H]noradenaline ([3H]NA) and [3H]serotonin ([3H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12 mM K+-evoked release of preloaded [3H]dopamine ([3H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1–1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K+-evoked, Ca2+-dependent, exocytotic-like release of [3H]5-HT and [3H]DA. At the same concentration, salvinorin A facilitated the 12 mM K+-evoked, Ca2+-dependent, exocytotic-like release of [3H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum κ-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1–100 nM) antagonized the inhibition of [3H]5-HT and [3H]DA exocytosis as well as the facilitation of [3H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1–100 nM) mimicked salvinorin A in inhibiting [3H]5-HT and of [3H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K+-evoked release of [3H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective μ opioid (MOR) receptor antagonist CTAP (10–100 nM), whereas facilitation of [3H]NA exocytosis, but not inhibition of [3H]5-HT and [3H]DA K+-evoked release, was counteracted by the δ opioid receptor (DOR) antagonist naltrindole (1–100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.