Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition.
Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition.
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DOI：
10.1523/jneurosci.2671-11.2011
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发表时间：
2011-10-12
期刊：
影响因子：
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通讯作者：
Chiou LC
中科院分区：
文献类型：
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作者：
Ho YC;Lee HJ;Tung LW;Liao YY;Fu SY;Teng SF;Liao HT;Mackie K;Chiou LC
食欲素A和B是已知通过OX 1和OX 2受体调节唤醒、进食和奖赏的下丘脑肽。食欲素在脑中也是抗伤害感受的，但它们的作用机制仍不清楚。在这里，我们研究了食欲素A在大鼠中脑导水管周围灰质（vlPAG）的抗伤害性机制，这是一个对启动下行疼痛抑制至关重要的中脑区域。在vlPAG切片中，食欲素A（30-300 nM）抑制GABA能诱发的抑制性突触后电流（IPSC）。这种作用被OX 1（SB 334867）拮抗剂阻断，但不被OX 2（化合物29）拮抗剂阻断。增食欲素A增加了成对IPSC的成对脉冲比，降低了微型IPSC的频率，但不降低振幅。食欲素A诱导的IPSC抑制由大麻素1（CB 1）受体激动剂WIN 55，212 -2模拟。CB 1拮抗剂AM 251可逆转两种激动剂的抑制作用。Orexin A诱导的IPSC抑制被U 73122和tetrahydrolipstatin（分别为磷脂酶C（PLC）和二酰基甘油脂肪酶（DAGL）的抑制剂）阻止，并被URB 602（其抑制2-花生四烯酰甘油（2-AG）的酶促降解）增强。在vlPAG中观察到中度DAGLα免疫反应性，但未观察到DAGLβ。食欲素A对诱发的突触后电位产生全面兴奋作用，从而增加vlPAG神经元活动。vlPAG内微量注射食欲素A以SB 334867和AM 251阻断的方式降低大鼠的热板伤害性反应。因此，食欲素A可能通过激活突触后OX 1受体，刺激2-AG（一种内源性大麻素）的合成，通过Gq蛋白介导的PLC-DAGLα酶级联反应，最终导致vlPAG中GABA释放的逆行抑制（去抑制），从而产生抗伤害感受。
Orexin A and B are hypothalamic peptides known to modulate arousal, feeding and reward via OX1 and OX2 receptors. Orexins are also antinociceptive in the brain but their mechanism(s) of action remain unclear. Here, we investigated the antinociceptive mechanism of orexin A in the rat ventrolateral periaqueductal gray (vlPAG), a midbrain region crucial for initiating descending pain inhibition. In vlPAG slices, orexin A (30-300 nM) depressed GABAergic evoked inhibitory postsynaptic currents (IPSCs). This effect was blocked by an OX1 (SB 334867), but not OX2 (Compound 29), antagonist. Orexin A increased the paired-pulse ratio of paired IPSCs, and decreased the frequency, but not amplitude, of miniature IPSCs. Orexin A-induced IPSC depression was mimicked by WIN 55,212-2, a cannabinoid 1 (CB1) receptor agonist. AM 251, a CB1 antagonist, reversed depressant effects by both agonists. Orexin A-induced IPSC depression was prevented by U73122 and tetrahydrolipstatin, inhibitors of phospholipase C (PLC) and diacylglycerol lipase (DAGL), respectively, and enhanced by URB602, which inhibits enzymatic degradation of 2-arachidonoylglycerol (2-AG). Moderate DAGLα, but not DAGLβ, immunoreactivity was observed in the vlPAG. Orexin A produced an overall excitatory effect on evoked postsynaptic potentials and hence increased vlPAG neuronal activity. Intra-vlPAG microinjection of orexin A reduced hot-plate nociceptive responses in rats in a manner blocked by SB 334867 and AM 251. Therefore, orexin A may produce antinociception by activating postsynaptic OX1 receptors, stimulating synthesis of 2-AG, an endocannabinoid, through a Gq-protein-mediated PLC-DAGLα enzymatic cascade culminating in retrograde inhibition of GABA release (disinhibition) in the vlPAG.