Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
J Neurosci. 2013 Apr 3;33(14):5881-94. doi: 10.1523/JNEUROSCI.4278-12.2013.
Pain is a complex experience composed of sensory and affective components. Although the neural systems of the sensory component of pain have been studied extensively, those of its affective component remain to be determined. In the present study, we examined the effects of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) injected into the dorsolateral bed nucleus of the stria terminalis (dlBNST) on pain-induced aversion and nociceptive behaviors in rats to examine the roles of these peptides in affective and sensory components of pain, respectively. In vivo microdialysis showed that formalin-evoked pain enhanced the release of CRF in this brain region. Using a conditioned place aversion (CPA) test, we found that intra-dlBNST injection of a CRF1 or CRF2 receptor antagonist suppressed pain-induced aversion. Intra-dlBNST CRF injection induced CPA even in the absence of pain stimulation. On the other hand, intra-dlBNST NPY injection suppressed pain-induced aversion. Coadministration of NPY inhibited CRF-induced CPA. This inhibitory effect of NPY was blocked by coadministration of a Y1 or Y5 receptor antagonist. Furthermore, whole-cell patch-clamp electrophysiology in dlBNST slices revealed that CRF increased neuronal excitability specifically in type II dlBNST neurons, whereas NPY decreased it in these neurons. Excitatory effects of CRF on type II dlBNST neurons were suppressed by NPY. These results have uncovered some of the neuronal mechanisms underlying the affective component of pain by showing opposing roles of intra-dlBNST CRF and NPY in pain-induced aversion and opposing actions of these peptides on neuronal excitability converging on the same target, type II neurons, within the dlBNST.
疼痛是一种由感觉和情感成分组成的复杂体验。尽管已经广泛研究了疼痛感觉成分的神经机制，但情感成分的神经机制仍有待确定。在本研究中，我们研究了向终纹床核背外侧区（dlBNST）内注射促肾上腺皮质释放因子（CRF）和神经肽 Y（NPY）对大鼠疼痛诱发厌恶和痛觉行为的影响，以分别研究这些肽在疼痛的情感和感觉成分中的作用。体内微透析显示福尔马林诱发的疼痛增强了该脑区 CRF 的释放。使用条件性位置厌恶（CPA）测试，我们发现 dlBNST 内注射 CRF1 或 CRF2 受体拮抗剂抑制了疼痛诱发的厌恶。dlBNST 内 CRF 注射甚至在没有疼痛刺激的情况下也会引起 CPA。另一方面，dlBNST 内 NPY 注射抑制了疼痛诱发的厌恶。NPY 的共给药抑制了 CRF 诱导的 CPA。这种 NPY 的抑制作用被共给药 Y1 或 Y5 受体拮抗剂阻断。此外，dlBNST 切片中的全细胞膜片钳电生理学显示，CRF 特异性增加了 II 型 dlBNST 神经元的兴奋性，而 NPY 则降低了其兴奋性。CRF 对 II 型 dlBNST 神经元的兴奋作用被 NPY 抑制。这些结果通过显示 dlBNST 内 CRF 和 NPY 在疼痛诱发厌恶中的作用相反，以及这些肽对神经元兴奋性的作用相反，共同作用于同一靶标，即 dlBNST 内的 II 型神经元，揭示了疼痛情感成分的一些神经元机制。
