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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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Enhanced NMDA receptor-mediated transmission after injury. (A) NMDA receptor-mediated mEPSCs recorded in PAG neurons at a holding potential of -30 mV. Representative traces show NMDA receptor-mediated mEPSCs in the saline, Hyp, CFA, and CFA + Hyp treated mouse. (B) Cumulative frequency (left) and amplitude (right) histogram of the mEPSCs from the cells in (A). Filled circles, from a saline control mouse; open circles, Hyp treated mouse; filled trangles, from a CFA-injected mouse; open trangles, from a CFA + Hyp treated mouse. (C) Summary of mEPSCs frequency (left) and amplitude (right) in neurons from the saline, Hyp, CFA, and CFA + Hyp treated mice. Values were significantly different from saline control * p < 0.05; from CFA-injected alone # p < 0.05.
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Figure 3: Enhanced NMDA receptor-mediated transmission after injury. (A) NMDA receptor-mediated mEPSCs recorded in PAG neurons at a holding potential of -30 mV. Representative traces show NMDA receptor-mediated mEPSCs in the saline, Hyp, CFA, and CFA + Hyp treated mouse. (B) Cumulative frequency (left) and amplitude (right) histogram of the mEPSCs from the cells in (A). Filled circles, from a saline control mouse; open circles, Hyp treated mouse; filled trangles, from a CFA-injected mouse; open trangles, from a CFA + Hyp treated mouse. (C) Summary of mEPSCs frequency (left) and amplitude (right) in neurons from the saline, Hyp, CFA, and CFA + Hyp treated mice. Values were significantly different from saline control * p < 0.05; from CFA-injected alone # p < 0.05.

Mentions: To test whether up-regulation of NR2B receptor leads to changes in NMDAR-mediated synaptic transmission, we measured NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) in the presence of CNQX (an AMPA receptor antagonist) in the lateral periaqueductal gray (LPAG). The amplitude, not the frequency of NMDAR-mediated mEPSCs was significantly increased at LPAG synapses of CFA-injected mice compared with saline controls (Frequency: saline, 0.38 ± 0.07 Hz, CFA, 0.45 ± 0.07 Hz, n = 8; amplitude: saline, 9.4 ± 1.0 pA, CFA, 13.8 ± 1.4 pA, n = 8, p < 0.05 vs saline; Fig. 3). As we predicted, Hyp reversed the enhanced NMDAR-mediated transmission in the PAG of CFA-injected mice (Frequency: 0.42 ± 0.05 Hz, n = 6; amplitude: 11.3 ± 1.1 pA, n = 8, p < 0.05 vs CFA-injected alone; Fig. 3). It suggests a possible mechanism for an enhancement in NMDAR function is an up-regulation of NR2B-containing NMDARs 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)

Enhanced NMDA receptor-mediated transmission after injury. (A) NMDA receptor-mediated mEPSCs recorded in PAG neurons at a holding potential of -30 mV. Representative traces show NMDA receptor-mediated mEPSCs in the saline, Hyp, CFA, and CFA + Hyp treated mouse. (B) Cumulative frequency (left) and amplitude (right) histogram of the mEPSCs from the cells in (A). Filled circles, from a saline control mouse; open circles, Hyp treated mouse; filled trangles, from a CFA-injected mouse; open trangles, from a CFA + Hyp treated mouse. (C) Summary of mEPSCs frequency (left) and amplitude (right) in neurons from the saline, Hyp, CFA, and CFA + Hyp treated mice. Values were significantly different from saline control * p < 0.05; from CFA-injected alone # p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Enhanced NMDA receptor-mediated transmission after injury. (A) NMDA receptor-mediated mEPSCs recorded in PAG neurons at a holding potential of -30 mV. Representative traces show NMDA receptor-mediated mEPSCs in the saline, Hyp, CFA, and CFA + Hyp treated mouse. (B) Cumulative frequency (left) and amplitude (right) histogram of the mEPSCs from the cells in (A). Filled circles, from a saline control mouse; open circles, Hyp treated mouse; filled trangles, from a CFA-injected mouse; open trangles, from a CFA + Hyp treated mouse. (C) Summary of mEPSCs frequency (left) and amplitude (right) in neurons from the saline, Hyp, CFA, and CFA + Hyp treated mice. Values were significantly different from saline control * p < 0.05; from CFA-injected alone # p < 0.05.
Mentions: To test whether up-regulation of NR2B receptor leads to changes in NMDAR-mediated synaptic transmission, we measured NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) in the presence of CNQX (an AMPA receptor antagonist) in the lateral periaqueductal gray (LPAG). The amplitude, not the frequency of NMDAR-mediated mEPSCs was significantly increased at LPAG synapses of CFA-injected mice compared with saline controls (Frequency: saline, 0.38 ± 0.07 Hz, CFA, 0.45 ± 0.07 Hz, n = 8; amplitude: saline, 9.4 ± 1.0 pA, CFA, 13.8 ± 1.4 pA, n = 8, p < 0.05 vs saline; Fig. 3). As we predicted, Hyp reversed the enhanced NMDAR-mediated transmission in the PAG of CFA-injected mice (Frequency: 0.42 ± 0.05 Hz, n = 6; amplitude: 11.3 ± 1.1 pA, n = 8, p < 0.05 vs CFA-injected alone; Fig. 3). It suggests a possible mechanism for an enhancement in NMDAR function is an up-regulation of NR2B-containing NMDARs 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