科研之友
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摘要
Background: Evidence indicates that the anesthetic-sparing effects of alpha(2)-adrenergic receptor (AR) agonists involve alpha(2A)-AR heteroreceptors on nonadrenergic neurons. Since volatile anesthetics inhibit neurotransmitter release by reducing synaptic vesicle (SV) exocytosis, the authors hypothesized that alpha(2)-AR agonists inhibit nonadrenergic SV exocytosis and thereby potentiate presynaptic inhibition of exocytosis by isoflurane. Methods: Quantitative imaging of fluorescent biosensors of action potential-evoked SV exocytosis (synaptophysin-pHluorin) and Ca2+ influx (GCaMP6) were used to characterize presynaptic actions of the clinically used alpha(2)-AR agonists dexmedetomidine and clonidine, and their interaction with isoflurane, in cultured rat hippocampal neurons. Results: Dexmedetomidine (0.1 mu M, n = 10) or clonidine (0.5 mu M, n = 8) inhibited action potential-evoked exocytosis (54 +/- 5% and 59 +/- 8% of control, respectively; P < 0.001). Effects on exocytosis were blocked by the subtype-nonselective alpha(2)-AR antagonist atipamezole or the alpha(2A)-AR-selective antagonist BRL 44408 but not by the alpha C-2-AR-selective antagonist JP 1302. Dexmedetomidine inhibited exocytosis and presynaptic Ca2+ influx without affecting Ca2+ coupling to exocytosis, consistent with an effect upstream of Ca2+-exocytosis coupling. Exocytosis coupled to both N-type and P/Q-type Ca2+ channels was inhibited by dexmedetomidine or clonidine. Dexmedetomidine potentiated inhibition of exocytosis by 0.7 mM isoflurane (to 42 +/- 5%, compared to 63 +/- 8% for isoflurane alone; P < 0.05). Conclusions: Hippocampal SV exocytosis is inhibited by alpha(2A)-AR activation in proportion to reduced Ca2+ entry. These effects are additive with those of isoflurane, consistent with a role for alpha(2A)-AR presynaptic heteroreceptor inhibition of nonadrenergic synaptic transmission in the anesthetic-sparing effects of alpha(2A)-AR agonists.
- 出版日期2016-9
