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The Journal of Neuroscience, March 11, 2009, 29(10):3307-3321; doi:10.1523/JNEUROSCI.4300-08.2009
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Cellular/Molecular
Activation of Extracellular Signal-Regulated Kinase in the Anterior Cingulate Cortex Contributes to the Induction and Expression of Affective Pain
Hong Cao,1 * Yong-Jing Gao,1,2 * Wen-Hua Ren,1 Ting-Ting Li,1 Kai-Zheng Duan,1 Yi-Hui Cui,3 Xiao-Hua Cao,3 Zhi-Qi Zhao,1 Ru-Rong Ji,2 andYu-Qiu Zhang1 1Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China, 2Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and 3Shanghai Institute of Brain Functional Genomics, Key Laboratory of Brain Functional Genomics, Ministry of Education, and Science and Technology Commission of Shanghai Municipality, East China Normal University, Shanghai 200062, China
Correspondence should be addressed to either of the following: Dr. Yu-Qiu Zhang, Institute of Neurobiology, Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China, Email: yuqiuzhang{at}fudan.edu.cn; or Ru-Rong Ji, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, Email: rrji{at}zeus.bwh.harvard.edu
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.
Received Sept. 9, 2008; revised Jan. 11, 2009; accepted Feb. 12, 2009.
Correspondence should be addressed to either of the following: Dr. Yu-Qiu Zhang, Institute of Neurobiology, Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China, Email: yuqiuzhang{at}fudan.edu.cn; or Ru-Rong Ji, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, Email: rrji{at}zeus.bwh.harvard.edu
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