Jin W, Chavkin C
Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195-7280, USA.
Brain Res. 1999 Mar 13;821(2):286-93. doi: 10.1016/s0006-8993(99)01089-6.
The cellular mechanisms underlying mu opioid facilitation of mossy fiber (MF) long-term potentiation (LTP) and synaptic transmission were investigated in the rat hippocampal slice. Naloxone (10 microM) significantly inhibited the induction of mossy fiber LTP, an effect attributed by Derrick and Martinez [B.E. Derrick, J.L.J. Martinez, Opioid receptor activation is one factor underlying the frequency dependence of mossy fiber LTP induction, J. Neurosci. 14 (1994) 4359-4367] to antagonism of endogenous opioid peptide action. We found that the inhibitory effects of naloxone were not blocked by bicuculline, suggesting that endogenous opioids did not enhance mossy fiber LTP by depressing GABAA inhibition. [d-Ala2, NMePhe4, Glyol5] enkephalin, DAMGO (300 nM), a mu opioid agonist, mimicked the action of endogenous opioids, enhancing both mossy fiber LTP induction and paired-pulse facilitation. DAMGO potentiation of the paired-pulse facilitation of mossy fiber response was also insensitive to bicuculline but was blocked by the mu selective antagonist CTOP. Further analysis of the cellular mechanism showed that the depletion of internal Ca2+ stores by thapsigargin (1 microM), or inhibition of protein kinases by application of staurosporine (1 microM) did not block the DAMGO facilitation of mossy fiber-CA3 synaptic transmission. However, application of phaclofen (100 microM GABAB receptor antagonist or SCH 50911, a more potent GABAB antagonist significantly inhibited the DAMGO effect (49+/-15%; 51+/-19% inhibition, P<0.05). The data indicate that the DAMGO effect on the mossy fiber pathway is partially mediated by a reduction in GABA activation of GABAB receptors. These findings further suggest that endogenous opioid peptides activate mu opioid receptors to facilitate mossy fiber LTP and synaptic transmission in rat hippocampus partially by GABAB receptor-mediated disinhibitory mechanism.
在大鼠海马切片中研究了μ阿片类物质促进苔藓纤维（MF）长时程增强（LTP）和突触传递的细胞机制。纳洛酮（10微摩尔）显著抑制苔藓纤维LTP的诱导，德里克和马丁内斯[B.E.德里克，J.L.J.马丁内斯，阿片受体激活是苔藓纤维LTP诱导频率依赖性的一个潜在因素，《神经科学杂志》14（1994）4359 - 4367]将此效应归因于内源性阿片肽作用的拮抗。我们发现纳洛酮的抑制作用未被荷包牡丹碱阻断，这表明内源性阿片类物质并非通过抑制GABAA抑制来增强苔藓纤维LTP。[d - Ala2，NMePhe4，Glyol5]脑啡肽、DAMGO（300纳摩尔），一种μ阿片类激动剂，模拟了内源性阿片类物质的作用，增强了苔藓纤维LTP诱导和双脉冲易化。DAMGO对苔藓纤维反应双脉冲易化的增强也对荷包牡丹碱不敏感，但被μ选择性拮抗剂CTOP阻断。对细胞机制的进一步分析表明，毒胡萝卜素（1微摩尔）耗尽细胞内钙库，或应用星形孢菌素（1微摩尔）抑制蛋白激酶，均未阻断DAMGO对苔藓纤维 - CA3突触传递的促进作用。然而，应用巴氯芬（100微摩尔GABAB受体拮抗剂）或SCH 50911，一种更强效的GABAB拮抗剂，显著抑制了DAMGO效应（抑制率分别为49±15%；51±19%，P < 0.05）。数据表明DAMGO对苔藓纤维通路的作用部分是通过降低GABAB受体的GABA激活来介导的。这些发现进一步表明内源性阿片肽激活μ阿片受体，部分通过GABAB受体介导的去抑制机制促进大鼠海马中的苔藓纤维LTP和突触传递。
