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A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain.

Hu J, Wang Z, Guo YY, Zhang XN, Xu ZH, Liu SB, Guo HJ, Yang Q, Zhang FX, Sun XL, Zhao MG - Mol Pain (2009)

Bottom Line: Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered.PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats.Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. hujing2@fmmu.edu.cn

ABSTRACT
The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

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Up-regulation of NR2B receptors in PAG after injury. (A) Western blot results showed that the expression level of GluR1 and NR2B receptors, but not NR2A receptor, was increased in the PAG after CFA injection. Hyp reversed expression level of GluR1 and NR2B receptors. (B) Summary of expression of NR2A, NR2B, GluR1 receptors in the PAG after CFA-injection. Values were significantly different from saline control ** p < 0.01; from CFA-injected alone # p < 0.05.
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Figure 1: Up-regulation of NR2B receptors in PAG after injury. (A) Western blot results showed that the expression level of GluR1 and NR2B receptors, but not NR2A receptor, was increased in the PAG after CFA injection. Hyp reversed expression level of GluR1 and NR2B receptors. (B) Summary of expression of NR2A, NR2B, GluR1 receptors in the PAG after CFA-injection. Values were significantly different from saline control ** p < 0.01; from CFA-injected alone # p < 0.05.

Mentions: Transgenic over-expression of NR2B-containing NMDARs in forebrain areas enhances inflammatory pain in mice [23]. Similarly, our previous results show that NR2B expression is increased in the anterior cingulated cortex after hindpaw CFA injection induced inflammatory pain [17]. As PAG plays important roles in processing pain-related information [1,6,20], it raises the possibility that NR2B expression is changed in the PAG after injury. To test this hypothesis, NR2B expression was examined by Western blot analysis on total PAG homogenates from mice. Western blot results showed that NR2B expression in PAG was notably increased at 3d after CFA-injection (234.4% ± 41.5% of saline, n = 6, p < 0.01; Fig. 1). Similar to NR2B, AMPA receptor GluR1 subunit expression was also increased after injury (189.4% ± 26.5% of saline, n = 6, p < 0.01; Fig. 1). However, no significant alteration was detected in the NR2A expression in the PAG after injury (Fig. 1). To further evaluate roles of NR2B receptor in inflammatory pain modulation, we treated CFA-injected mice with Hyp which shows anti-inflammatory and analgesic activities [22]. NR2B expression was significantly reduced in the PAG of CFA-injected mice administrated with Hyp (100 mg/kg, i.g. twice daily for 3 days) (132.1% ± 26.8% saline, n = 6, p < 0.05 vs CFA-injected alone; Fig. 1B). These findings imply that changes in NMDARs are selective for NR2B subunit in the PAG.


A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain.

Hu J, Wang Z, Guo YY, Zhang XN, Xu ZH, Liu SB, Guo HJ, Yang Q, Zhang FX, Sun XL, Zhao MG - Mol Pain (2009)

Up-regulation of NR2B receptors in PAG after injury. (A) Western blot results showed that the expression level of GluR1 and NR2B receptors, but not NR2A receptor, was increased in the PAG after CFA injection. Hyp reversed expression level of GluR1 and NR2B receptors. (B) Summary of expression of NR2A, NR2B, GluR1 receptors in the PAG after CFA-injection. Values were significantly different from saline control ** p < 0.01; from CFA-injected alone # p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803476&req=5

Figure 1: Up-regulation of NR2B receptors in PAG after injury. (A) Western blot results showed that the expression level of GluR1 and NR2B receptors, but not NR2A receptor, was increased in the PAG after CFA injection. Hyp reversed expression level of GluR1 and NR2B receptors. (B) Summary of expression of NR2A, NR2B, GluR1 receptors in the PAG after CFA-injection. Values were significantly different from saline control ** p < 0.01; from CFA-injected alone # p < 0.05.
Mentions: Transgenic over-expression of NR2B-containing NMDARs in forebrain areas enhances inflammatory pain in mice [23]. Similarly, our previous results show that NR2B expression is increased in the anterior cingulated cortex after hindpaw CFA injection induced inflammatory pain [17]. As PAG plays important roles in processing pain-related information [1,6,20], it raises the possibility that NR2B expression is changed in the PAG after injury. To test this hypothesis, NR2B expression was examined by Western blot analysis on total PAG homogenates from mice. Western blot results showed that NR2B expression in PAG was notably increased at 3d after CFA-injection (234.4% ± 41.5% of saline, n = 6, p < 0.01; Fig. 1). Similar to NR2B, AMPA receptor GluR1 subunit expression was also increased after injury (189.4% ± 26.5% of saline, n = 6, p < 0.01; Fig. 1). However, no significant alteration was detected in the NR2A expression in the PAG after injury (Fig. 1). To further evaluate roles of NR2B receptor in inflammatory pain modulation, we treated CFA-injected mice with Hyp which shows anti-inflammatory and analgesic activities [22]. NR2B expression was significantly reduced in the PAG of CFA-injected mice administrated with Hyp (100 mg/kg, i.g. twice daily for 3 days) (132.1% ± 26.8% saline, n = 6, p < 0.05 vs CFA-injected alone; Fig. 1B). These findings imply that changes in NMDARs are selective for NR2B subunit in the PAG.

Bottom Line: Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered.PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats.Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. hujing2@fmmu.edu.cn

ABSTRACT
The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

Show MeSH
Related in: MedlinePlus