Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain.
Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain.
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前扣带皮层细胞外信号调节激酶的激活有助于情感疼痛的诱导和表达
DOI：
10.1523/jneurosci.4300-08.2009
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发表时间：
2009-03-11
期刊：
影响因子：
--
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Cao H;Gao YJ;Ren WH;Li TT;Duan KZ;Cui YH;Cao XH;Zhao ZQ;Ji RR;Zhang YQ
前扣带皮层（ACC）参与对伤害性刺激的情感反应。然而，人们对所涉及的分子机制知之甚少。本研究表明，ACC细胞外信号调节激酶（ERK）的激活在疼痛相关的负性情绪中起着至关重要的作用。足底注射福尔马林后，双侧前扣带（rACC）的V-VI层和II-III层出现短暂的ERK激活和持续的ERK激活。使用福尔马林诱导的大鼠条件性位置回避（F-CPA），这被认为是反映了疼痛相关的负面情绪，我们发现，ERK激活的阻断与MEK抑制剂的rACC阻止F-CPA的诱导。有趣的是，这种封锁并不影响福尔马林诱导的两个阶段的自发伤害性反应和CPA收购引起的电足电击或U69，593，一种无害的厌恶剂。上游，NMDA受体，腺苷酸环化酶（AC）和磷酸激酶A（PKA）激活剂激活ERK在rACC切片。一致地，rACC内显微注射AC或PKA抑制剂阻止F-CPA诱导。下游，cAMP反应元件结合蛋白（CREB）的磷酸化诱导的rACC福尔马林注射和NMDA，AC和PKA激活剂在脑切片，这是由MEK抑制剂抑制。此外，ERK还参与了疼痛相关负性情绪的表达。因此，当大鼠再次暴露于条件反射环境中以恢复疼痛体验时，rACC中的ERK和CREB被重新激活，抑制ERK激活可阻断F-CPA的表达。总之，我们的研究结果表明，ERK在rACC激活是必要的疼痛相关的负面影响的诱导和表达。
The anterior cingulate cortex (ACC) is implicated in the affective response to noxious stimuli. However, little is known about the molecular mechanisms involved. The present study demonstrated that extracellular signal-regulated kinase (ERK) activation in the ACC plays a crucial role in pain-related negative emotion. Intraplantar formalin injection produced a transient ERK activation in laminae V-VI and a persistent ERK activation in laminae II-III of the rostral ACC (rACC) bilaterally. Using formalin-induced conditioned place avoidance (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that blockade of ERK activation in the rACC with MEK inhibitors prevented the induction of F-CPA. Interestingly, this blockade did not affect formalin-induced two-phase spontaneous nociceptive responses and CPA acquisition induced by electric foot-shock or U69,593, an innocuous aversive agent. Upstream, NMDA receptor, adenylyl cyclase (AC) and phosphokinase A (PKA) activators activated ERK in rACC slices. Consistently, intra-rACC microinjection of AC or PKA inhibitors prevented F-CPA induction. Downstream, phosphorylation of cAMP response element binding protein (CREB) was induced in the rACC by formalin injection and by NMDA, AC and PKA activators in brain slices, which was suppressed by MEK inhibitors. Furthermore, ERK also contributed to the expression of pain-related negative emotion. Thus, when rats were re-exposed to the conditioning context for retrieval of pain experience, ERK and CREB were reactivated in the rACC, and inhibiting ERK activation blocked the expression of F-CPA. All together, our results demonstrate that ERK activation in the rACC is required for the induction and expression of pain-related negative affect.