Noradrenergic alpha 2 receptor attenuated inflammatory pain through STEP61/ERK signalling

doi:10.1002/ejp.660

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	Noradrenergic alpha 2 receptor attenuated inflammatory pain through STEP61/ERK signalling
	Xu, YM; Wang, XT; Zhang, ZY; Suo, ZW; Yang, X; Hu, XD; Hu, XD (reprint author), Lanzhou Univ, Sch Pharm, Dept Mol Pharmacol, Lanzhou 730000, Gansu, Peoples R China.
刊名	EUROPEAN JOURNAL OF PAIN
	2015-10
卷号	19 期号:9 页码:1298-1307
ISSN号	1090-3801
DOI	10.1002/ejp.660
文献子类	Article
英文摘要	Background: Activation of noradrenergic alpha 2 receptor in spinal dorsal horn effectively alleviates the pathological pain. However, the precise mechanisms underlying noradrenergic pain suppression are not fully understood. Convincing evidence has indicated that extracellular signal-regulated kinases 1 and 2 (ERK1/2) play a key role in spinal sensitization. The present study investigated the potential influence of noradrenergic alpha 2 receptor agonist clonidine on ERK1/2 activity. Method: Clonidine was intrathecally given after intraplantar injection of complete Freund's adjuvant (CFA) in mice. The possible changes of ERK1/2 signalling were detected by Western blot, immunohistochemistry, co-immunoprecipitation and behavioural tests. Results: CFA significantly enhanced ERK1/2 activity in spinal dorsal horn, which was, however, greatly attenuated by clonidine application. Pretreatment with pertussis toxin abolished the inhibitory effect of clonidine on ERK1/2, suggesting the involvement of Gi alpha subunit (Gi protein). Noradrenergic alpha 2 receptor/Gi protein might repress ERK1/2 through cAMP-dependent protein kinase (PKA) pathway, because direct ERK1/2 activation by PKA agonist forskolin was also suppressed by clonidine. We found that 61 kD isoform of striatal-enriched protein phosphatase (STEP61) was a key intermediary for alpha 2 receptor/Gi protein/PKA signalling to manipulate ERK1/2 activity. By reducing PKA-mediated phosphorylation of STEP61 at Ser221, clonidine significantly resumed the inhibition conferred by STEP61 on ERK1/2. Direct expression of STEP61 mutant devoid of Ser221 phosphorylation mimicked clonidine by inhibiting ERK1/2 and pain sensitization in CFA-injected mice. Conclusion: The analgesic action produced by noradrenergic alpha 2 receptor agonist clonidine involved the reversal of ERK1/2 hyperactivity in spinal dorsal horn of inflamed mice.
学科主题	Anesthesiology ; Neurosciences & Neurology
出版地	HOBOKEN
资助项目	国家自然科学基金项目
项目编号	National Natural Science Foundation of China [31271186, 31100804]
语种	英语
WOS记录号	WOS:000362691300010
资助机构	NSFC
内容类型	期刊论文
源URL	[http://ir.lzu.edu.cn/handle/262010/179560]
专题	药学院_期刊论文
通讯作者	Hu, XD (reprint author), Lanzhou Univ, Sch Pharm, Dept Mol Pharmacol, Lanzhou 730000, Gansu, Peoples R China.
推荐引用方式 GB/T 7714	Xu, YM,Wang, XT,Zhang, ZY,et al. Noradrenergic alpha 2 receptor attenuated inflammatory pain through STEP61/ERK signalling[J]. EUROPEAN JOURNAL OF PAIN,2015,19(9):1298-1307.
APA	Xu, YM.,Wang, XT.,Zhang, ZY.,Suo, ZW.,Yang, X.,...&Hu, XD .(2015).Noradrenergic alpha 2 receptor attenuated inflammatory pain through STEP61/ERK signalling.EUROPEAN JOURNAL OF PAIN,19(9),1298-1307.
MLA	Xu, YM,et al."Noradrenergic alpha 2 receptor attenuated inflammatory pain through STEP61/ERK signalling".EUROPEAN JOURNAL OF PAIN 19.9(2015):1298-1307.