Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep15945
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Funding
- National Natural Science Foundation of China [31271258, 81571063, 81230024, 81200852, 81171056, 81371229]
- Natural Science Funding for Colleges and Universities in Jiangsu Province [12KJB320010]
- Suzhou Science and Technology Development Plan [SYS201037, SYS201102]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars of State Education Ministry
- State Key Laboratory of Neuroscience of Chinese Academy of Sciences [SKLN-201502]
- 333 High Level Talent Cultivation Project of Jiangsu Province [BRA2015388]
- Soochow University
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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The arcuate nucleus (ARC) of the hypothalamus plays a key role in pain processing. Although it is well known that inhibition of NMDA receptor (NMDAR) in ARC attenuates hyperalgesia induced by peripheral inflammation, the underlying mechanism of NMDAR activation in ARC remains unclear. Protein kinase C (PKC) is involved in several signalling cascades activated in physiological and pathological conditions. Therefore, we hypothesised that upregulation of PKC activates NMDARs in the ARC, thus contributing to inflammatory hyperalgesia. Intra-ARC injection of chelerythrine (CC), a specific PKC inhibitor, attenuated complete Freund's adjuvant (CFA) induced thermal and mechanical hyperalgesia in a dose-dependent manner. In vivo extracellular recordings showed that microelectrophoresis of CC or MK-801 (a NMDAR antagonist) significantly reduced the enhancement of spontaneous discharges and pain-evoked discharges of ARC neurons. In addition, CFA injection greatly enhanced the expression of total and phosphorylated PKC gamma in the ARC. Interestingly, CFA injection also remarkably elevated the level of phosphorylated NR2B (Tyr1472) without affecting the expression of total NR2B. Importantly, intra-ARC injection of CC reversed the upregulation of phosphorylated NR2B subunits in the ARC. Taken together, peripheral inflammation leads to an activation of NMDARs mediated by PKC activation in the ARC, thus producing thermal and mechanical hyperalgesia.
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