Activation of adenylate cyclase-cyclic AMP-protein kinase A signaling by corticotropin-releasing factor within the dorsolateral bed nucleus of the stria terminalis is involved in pain-induced aversion.
Activation of adenylate cyclase-cyclic AMP-protein kinase A signaling by corticotropin-releasing factor within the dorsolateral bed nucleus of the stria terminalis is involved in pain-induced aversion.
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终纹背外侧床核内促肾上腺皮质激素释放因子激活腺苷酸环化酶-环 AMP-蛋白激酶 A 信号传导参与疼痛诱发的厌恶。
DOI：
10.1111/ejn.13419
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Minami M
中科院分区：
文献类型：
--
作者：
Kaneko T;Kaneda K;Ohno A;Takahashi D;Hara T;Amano T;Ide S;Yoshioka M;Minami M
疼痛是一种涉及感官和情感成分的复杂体验。尽管疼痛的感觉成分背后的神经元机制已经被广泛研究，但其情感成分背后的神经元机制尚未被阐明。最近，我们报道了促肾上腺皮质激素释放因子（CRF）诱导的终纹背外侧床核（dlBNST） II型神经元去极化对大鼠疼痛诱导的厌恶反应至关重要。然而，CRF兴奋作用背后的细胞内信号以及这种信号对诱导疼痛诱导的厌恶的贡献尚不清楚。在本研究中，我们通过对大鼠脑切片进行全细胞膜片钳记录和进行行为药理学分析来解决这些问题。蛋白激酶A （PKA）抑制剂Rp -环腺苷单磷硫酸酯（Rp - camp）或KT5720在细胞内灌注抑制CRF在II型dlBNST神经元中的兴奋作用，Rp - camp也抑制CRF的兴奋作用。此外，福斯克林（一种腺苷酸环化酶（AC）活化剂）的浴液应用模拟了CRF的作用，福斯克林预处理降低了CRF的兴奋作用。此外，条件场所厌恶（CPA）测试表明，Rp - camp与CRF共同作用于dlBNST可抑制CRF诱导的CPA。脑内注射Rp - cAMPS也能抑制疼痛诱导的CPA。这些结果表明，CRF通过激活AC - cAMP - PKA通路增加II型dlBNST神经元的兴奋性，从而引起疼痛诱导的厌恶反应。本研究结果揭示了疼痛负性情感成分的神经机制，并可能为治疗伴有心理因素的顽固性疼痛提供治疗靶点。
Pain is a complex experience involving sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been extensively studied, those underlying its affective component have yet to be elucidated. Recently, we reported that corticotrophin‐releasing factor (CRF)‐induced depolarization in type II neurons within the dorsolateral bed nucleus of the stria terminalis (dlBNST) is critical for pain‐induced aversive responses in rats. However, the intracellular signaling underlying the excitatory effects of CRF and the contribution of such signaling to the induction of pain‐induced aversion remain unclear. In the present study, we addressed these issues by conducting whole‐cell patch‐clamp recordings in rat brain slices and by undertaking behavioral pharmacological analyses. Intracellular perfusion of protein kinase A (PKA) inhibitor Rp‐cyclic adenosine monophosphorothioate (Rp‐cAMPS) or KT5720 suppressed the excitatory effects of CRF in type II dlBNST neurons, and bath application of Rp‐cAMPS also suppressed it. In addition, bath application of forskolin, an adenylate cyclase (AC) activator, mimicked the effects of CRF, and pretreatment with forskolin diminished the excitatory effects of CRF. Furthermore, a conditioned place aversion (CPA) test showed that co‐administration of Rp‐cAMPS with CRF into the dlBNST suppressed CRF‐induced CPA. Intra‐dlBNST injection of Rp‐cAMPS also suppressed pain‐induced CPA. These results suggest that CRF increases excitability of type II dlBNST neurons through activation of the AC‐cAMP‐PKA pathway, thereby causing pain‐induced aversive responses. The present findings shed light on the neuronal mechanisms underlying the negative affective component of pain and may provide therapeutic targets for treating intractable pain accompanied by psychological factors.