Cingulate Alpha-2A Adrenoceptors Mediate the Effects of Clonidine on Spontaneous Pain Induced by Peripheral Nerve Injury

Yong-Jie Wang; Zhen-Xing Zuo; Cheng Wu; Li Liu; Zhi-Hui Feng; Xiang-Yao Li

doi:10.3389/fnmol.2017.00289

Cingulate Alpha-2A Adrenoceptors Mediate the Effects of Clonidine on Spontaneous Pain Induced by Peripheral Nerve Injury

Front Mol Neurosci. 2017 Sep 12:10:289. doi: 10.3389/fnmol.2017.00289. eCollection 2017.

Authors

Yong-Jie Wang^{1

2}, Zhen-Xing Zuo³, Cheng Wu⁴, Li Liu⁵, Zhi-Hui Feng^{1

2}, Xiang-Yao Li⁴

Affiliations

¹ Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong UniversityXi'an, China.
² The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong UniversityXi'an, China.
³ Department of Surgery, Tongji Hospital, School of Medicine, Tongji UniversityShanghai, China.
⁴ Department of Physiology, Institute of Neuroscience, School of Medicine, Zhejiang UniversityHangzhou, China.
⁵ Core Facility of School of Medicine, Zhejiang UniversityHangzhou, China.

Abstract

The anterior cingulate cortex (ACC) is an important brain area for the regulation of neuropathic pain. The α_2A adrenoceptor is a good target for pain management. However, the role of cingulate α_2A adrenoceptors in the regulation of neuropathic pain has been less studied. In this study, we investigated the involvement of cingulate α_2A adrenoceptors in the regulation of neuropathic pain at different time points after peripheral nerve injury in mice. The application of clonidine, either systemically (0.5 mg/kg intraperitoneally) or specifically to the ACC, increased paw withdrawal thresholds (PWTs) and induced conditioned place preference (CPP) at day 7 after nerve injury, suggesting that cingulate α₂ adrenoceptors are involved in the regulation of pain-like behaviors. Quantitative real-time PCR data showed that α_2A adrenoceptors are the dominant α₂ adrenoceptors in the ACC. Furthermore, the expression of cingulate α_2A adrenoceptors was increased at day 3 and day 7 after nerve injury, but decreased at day 14, while no change was detected in the concentration of adrenaline or noradrenaline. BRL-44408 maleate, a selective antagonist of α_2A adrenoceptors, was microinfused into the ACC. This blocking of cingulate α_2A adrenoceptors activity abolished the CPP induced by clonidine (0.5 mg/kg intraperitoneally) but not the effects on PWTs at day 7. However, clonidine applied systemically or specifically to the ACC at day 14 increased the PWTs but failed to induce CPP; this negative effect was reversed by the overexpression of cingulate α_2A adrenoceptors. These results suggest that cingulate α_2A adrenoceptors are necessary for the analgesic effects of clonidine on spontaneous pain.

Keywords: anterior cingulate cortex; clonidine; conditioned place preference; mechanical allodynia; peripheral nerve injury; spontaneous pain; stage-dependance; α2A adrenoceptors.