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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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Changes in the PWL by AP-5 and Ro 25-6981. (A) Representative coronal section of rat midbrain showing PAG injection sites. Scale bar, 500 μm. Aq: aqueduct; DMPAG: Dorsomed periaqueductal gray; LPAG: Lateral periaqueductal gray. (B) PWL in the CFA-treated paws (ipsilateral) by AP-5 and Ro25-6981 infusion. (C) PWL in the right hind paws (contralateral) by AP-5 and Ro25-6981 infusion. Values were significantly different from saline control * p < 0.05, ** p < 0.01; from CFA-injected alone # p < 0.05.
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Figure 5: Changes in the PWL by AP-5 and Ro 25-6981. (A) Representative coronal section of rat midbrain showing PAG injection sites. Scale bar, 500 μm. Aq: aqueduct; DMPAG: Dorsomed periaqueductal gray; LPAG: Lateral periaqueductal gray. (B) PWL in the CFA-treated paws (ipsilateral) by AP-5 and Ro25-6981 infusion. (C) PWL in the right hind paws (contralateral) by AP-5 and Ro25-6981 infusion. Values were significantly different from saline control * p < 0.05, ** p < 0.01; from CFA-injected alone # p < 0.05.

Mentions: Our results show that NR2B expression is increased in the PAG after peripheral injury, suggesting that inhibition of the NR2B subunit may alter inflammation -induced behavioral responses. To test this hypothesis, we microinjected AP-5 (an NMDAR antagonist) and Ro 25-6981 (a selective NR2B antagonist) into the PAG of rats and evaluated the effects on thermal hyperalgesia induced by CFA-injection (Fig. 5A). The paw withdrawal latency (PWL) to thermal radian heat stimuli is a widely used nociceptive measure to study hyperalgesic behavior. As illustrated in Fig. 5, CFA-treated ipsilateral paws (left) showed a significant decrease in PWL when compared to left paws of control rats (from 12.6 ± 1.2 s to 6.8 ± 0.7 s, n = 10, p < 0.01 vs CFA-injected alone; Fig. 5B). Interestingly, PWL in contralateral paws (right) also showed a slight decrease when compared to right paws of control rats (from 12.9 ± 1.4 s to 9.8 ± 1.0 s; n = 11, p < 0.05 vs CFA-injected alone; Fig. 5C). Microinjection of Ap-5 (0.5 μg/0.5 μl) into the PAG induced a significant increase in PWL in CFA injected rats (ipsilateral: 11.8 ± 1.2 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5B; contralateral: 12.1 ± 1.4 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5C). Similar results were observed for PWL with the microinjection of Ro 25-6981(0.5 μg/0.5 μl) into the PAG (ipsilateral: 11.2 ± 1.1 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5B; contralateral: 11.5 ± 1.6 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5C).


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)

Changes in the PWL by AP-5 and Ro 25-6981. (A) Representative coronal section of rat midbrain showing PAG injection sites. Scale bar, 500 μm. Aq: aqueduct; DMPAG: Dorsomed periaqueductal gray; LPAG: Lateral periaqueductal gray. (B) PWL in the CFA-treated paws (ipsilateral) by AP-5 and Ro25-6981 infusion. (C) PWL in the right hind paws (contralateral) by AP-5 and Ro25-6981 infusion. Values were significantly different from saline control * p < 0.05, ** p < 0.01; from CFA-injected alone # p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 5: Changes in the PWL by AP-5 and Ro 25-6981. (A) Representative coronal section of rat midbrain showing PAG injection sites. Scale bar, 500 μm. Aq: aqueduct; DMPAG: Dorsomed periaqueductal gray; LPAG: Lateral periaqueductal gray. (B) PWL in the CFA-treated paws (ipsilateral) by AP-5 and Ro25-6981 infusion. (C) PWL in the right hind paws (contralateral) by AP-5 and Ro25-6981 infusion. Values were significantly different from saline control * p < 0.05, ** p < 0.01; from CFA-injected alone # p < 0.05.
Mentions: Our results show that NR2B expression is increased in the PAG after peripheral injury, suggesting that inhibition of the NR2B subunit may alter inflammation -induced behavioral responses. To test this hypothesis, we microinjected AP-5 (an NMDAR antagonist) and Ro 25-6981 (a selective NR2B antagonist) into the PAG of rats and evaluated the effects on thermal hyperalgesia induced by CFA-injection (Fig. 5A). The paw withdrawal latency (PWL) to thermal radian heat stimuli is a widely used nociceptive measure to study hyperalgesic behavior. As illustrated in Fig. 5, CFA-treated ipsilateral paws (left) showed a significant decrease in PWL when compared to left paws of control rats (from 12.6 ± 1.2 s to 6.8 ± 0.7 s, n = 10, p < 0.01 vs CFA-injected alone; Fig. 5B). Interestingly, PWL in contralateral paws (right) also showed a slight decrease when compared to right paws of control rats (from 12.9 ± 1.4 s to 9.8 ± 1.0 s; n = 11, p < 0.05 vs CFA-injected alone; Fig. 5C). Microinjection of Ap-5 (0.5 μg/0.5 μl) into the PAG induced a significant increase in PWL in CFA injected rats (ipsilateral: 11.8 ± 1.2 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5B; contralateral: 12.1 ± 1.4 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5C). Similar results were observed for PWL with the microinjection of Ro 25-6981(0.5 μg/0.5 μl) into the PAG (ipsilateral: 11.2 ± 1.1 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5B; contralateral: 11.5 ± 1.6 s, n = 5, p < 0.05 vs saline microinjection, Fig. 5C).

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