Deyama Satoshi, Sugano Yaya, Mori Sakura, Amano Taiju, Yoshioka Mitsuhiro, Kaneda Katsuyuki, Minami Masabumi
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Neuropharmacology. 2017 May 15;118:59-68. doi: 10.1016/j.neuropharm.2017.03.008. Epub 2017 Mar 9.
Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate-nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test. Intra-vBNST injection of either CNQX (an AMPA receptor antagonist) or MK-801 (an NMDA receptor antagonist) dose-dependently attenuated intraplantar formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. In vivo microdialysis showed that extracellular oxidative NO metabolites (NOx) levels were significantly increased by intraplantar formalin injection. Intra-vBNST injection of NPLA (a selective neuronal NO synthase (nNOS) inhibitor), c-PTIO (a NO scavenger), or ZL006 (a postsynaptic density-95 (PSD-95)-nNOS interaction inhibitor) dose-dependently suppressed F-CPA without attenuating nociceptive behaviors. Intra-vBNST injection of NOR3 (a NO donor) produced CPA in a dose-dependent manner in the absence of noxious stimulation. Furthermore, whole-cell patch-clamp electrophysiology in the vBNST slices revealed that NOR3 induced depolarization of hyperpolarization-activated cation current (I)-positive vBNST neurons, which was blocked by the NO scavenger. These results suggest that activation of glutamatergic transmission and subsequent nNOS-derived NO production within the vBNST mediate the negative affective component of pain and that NO-evoked excitation of I-positive vBNST neurons may be among the cellular mechanisms underlying pain-induced aversion.
疼痛由感觉和情感成分组成。尽管对疼痛感觉成分背后的神经元机制已进行了广泛研究，但其情感成分背后的机制才刚刚开始被阐明。此前，我们已表明终纹床核腹侧部分（vBNST）在疼痛的负面情感成分中起关键作用。在此，我们使用条件性位置厌恶（CPA）试验研究了谷氨酸-一氧化氮（NO）信号在大鼠疼痛情感成分中的作用。向vBNST内注射CNQX（一种AMPA受体拮抗剂）或MK-801（一种NMDA受体拮抗剂）均剂量依赖性地减弱了足底注射福尔马林诱导的CPA（F-CPA），而不降低伤害性反应行为。体内微透析显示，足底注射福尔马林可使细胞外氧化型NO代谢产物（NOx）水平显著升高。向vBNST内注射NPLA（一种选择性神经元型一氧化氮合酶（nNOS）抑制剂）、c-PTIO（一种NO清除剂）或ZL006（一种突触后致密蛋白95（PSD-95）-nNOS相互作用抑制剂）均剂量依赖性地抑制F-CPA，而不减弱伤害性反应行为。在无有害刺激的情况下，向vBNST内注射NOR3（一种NO供体）以剂量依赖性方式产生CPA。此外，vBNST切片的全细胞膜片钳电生理学显示，NOR3诱导超极化激活阳离子电流（I）阳性的vBNST神经元去极化，该效应被NO清除剂阻断。这些结果表明，vBNST内谷氨酸能传递的激活以及随后nNOS衍生的NO生成介导了疼痛的负面情感成分，并且NO诱发的I阳性vBNST神经元兴奋可能是疼痛诱导厌恶的细胞机制之一。
