Contributions of the Ventrolateral Orbital Cortex to Pain-Related Negative Emotion

Su-Jie Ni1, Dong Zhou1, Hong Cao1, Zhi-Qi Zhao1, Yu-Ping Peng2, Yu-Qiu Zhang*, 1
1 Institute of Neurobiology,Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
2 Department of Biological Science and Technology, Nantong University,Nantong, Jiangsu, 210093

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© 2009 Ni et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Institute of Neurobiology,Fudan University, 138 Yixueyuan Road, Shanghai 200032, China. Tel: 86-21-54237635; Fax: 86-21-54237647;


Painful stimuli evoke pain sensation and unpleasant emotional feelings. Recent studies demonstrated that the anterior cingulate cortex (ACC) and amygdala play a crucial role in pain-related negative emotion using a rat formalininduced conditioned place aversion (F-CPA) model, a nociceptor-driven, associative avoidance-learning assay, which was considered as a direct reflection of negative emotion of pain. In this study, we further revealed the role of the ventrolateral orbital cortex (VLO) in pain-related negative emotion. Electrolytic or chemical lesion of the bilateral VLO abolished FCPA. Interestingly, this lesion affected neither acute formalin-induced two-phase spontaneous nociceptive behaviors nor low-intensity electric foot shock-induced CPA (S-CPA). Furthermore, we showed that formalin nociceptive conditioning induced a persistent (>24 hrs) cAMP response element binding protein (CREB) phosphorylation (pCREB) and an accompanying increase in Fos expression in the bilateral VLO. Re-exposing rats to the nociceptive conditioning context for retrieval of pain experience produced upregulation of pCREB and Fos expression in the bilateral VLO also. These results provided direct evidence indicating that the VLO is required for pain-related aversion, and also suggested a role for CREB phosphorylation in the induction of pain-related aversion and reconsolidation of pain-related aversive memory following pain experience retrieval. Taking the present study together with the previous reports, it is reasonable/advisable to accept the proposal that a neural network of the VLO with the ACC, amygdala and perhaps some other limbic structures contributes to the negative emotion of pain. Thus, a multidisciplinary integrated approach to preventing chronic pain-induced emotional disturbance might be raised.

Keywords: Ventrolateral Orbital Cortex (VLO), VLO Lesion, Pain, Pain-Related, Negative Emotion, Formalin-induced conditioned place aversion (F-CPA), F-CPA Retrieval, Formalin-Induced Acute Nociceptive Behavior, CAMP Response Element Binding Protein (CREB), Fos, Rat.