title: Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.
abstract: We investigated the effects of salvinorin A on the basal and the 12 mM K(+)-evoked release of preloaded [(3)H]noradenaline ([(3)H]NA) and [(3)H]serotonin ([(3)H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12mM K(+)-evoked release of preloaded [(3)H]dopamine ([(3)H]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, Ca(2+)-dependent, exocytotic-like release of [(3)H]5-HT and [(3)H]DA. At the same concentration, salvinorin A facilitated the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1-100 nM) antagonized the inhibition of [(3)H]5-HT and [(3)H]DA exocytosis as well as the facilitation of [(3)H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1-100 nM) mimicked salvinorin A in inhibiting [(3)H]5-HT and of [(3)H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K(+)-evoked release of [(3)H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective mu opioid (MOR) receptor antagonist CTAP (10-100 nM), whereas facilitation of [(3)H]NA exocytosis, but not inhibition of [(3)H]5-HT and [(3)H]DA K(+)-evoked release, was counteracted by the delta 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.
authors.affiliation: Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, 16148 Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Grilli
authors.forename: Elisa
authors.initials: E
authors.lastname: Neri
authors.forename: Stefania
authors.initials: S
authors.lastname: Zappettini
authors.forename: Francesca
authors.initials: F
authors.lastname: Massa
authors.forename: Angela
authors.initials: A
authors.lastname: Bisio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romussi
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D011957:Receptors, Opioid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D002491:Central Nervous System Agents; D045785:Diterpenes, Clerodane; D009292:Narcotic Antagonists; D018377:Neurotransmitter Agents; D011957:Receptors, Opioid; D012701:Serotonin; D011188:Potassium; D002118:Calcium; C090499:salvinorin A; D004298:Dopamine; D009638:Norepinephrine