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NAAG peptidase inhibition in the periaqueductal gray and rostral ventromedial medulla reduces flinching in the formalin model of inflammation.

Yamada T, Zuo D, Yamamoto T, Olszewski RT, Bzdega T, Moffett JR, Neale JH - Mol Pain (2012)

Bottom Line: The group II mGluR antagonist LY341495 blocked these effects of ZJ43 on the PAG and RVM.NAAG peptidase inhibition in the PAG and RVM did not affect the thermal withdrawal response in the hot plate test.Footpad inflammation also induced a significant increase in glutamate release in the PAG.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Georgetown University, Washington, DC, USA.

ABSTRACT

Background: Metabotropic glutamate receptors (mGluRs) have been identified as significant analgesic targets. Systemic treatments with inhibitors of the enzymes that inactivate the peptide transmitter N-acetylaspartylglutamate (NAAG), an mGluR3 agonist, have an analgesia-like effect in rat models of inflammatory and neuropathic pain. The goal of this study was to begin defining locations within the central pain pathway at which NAAG activation of its receptor mediates this effect.

Results: NAAG immunoreactivity was found in neurons in two brain regions that mediate nociceptive processing, the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM). Microinjection of the NAAG peptidase inhibitor ZJ43 into the PAG contralateral, but not ipsilateral, to the formalin injected footpad reduced the rapid and slow phases of the nociceptive response in a dose-dependent manner. ZJ43 injected into the RVM also reduced the rapid and slow phase of the response. The group II mGluR antagonist LY341495 blocked these effects of ZJ43 on the PAG and RVM. NAAG peptidase inhibition in the PAG and RVM did not affect the thermal withdrawal response in the hot plate test. Footpad inflammation also induced a significant increase in glutamate release in the PAG. Systemic injection of ZJ43 increased NAAG levels in the PAG and RVM and blocked the inflammation-induced increase in glutamate release in the PAG.

Conclusion: These data demonstrate a behavioral and neurochemical role for NAAG in the PAG and RVM in regulating the spinal motor response to inflammation and that NAAG peptidase inhibition has potential as an approach to treating inflammatory pain via either the ascending (PAG) and/or the descending pain pathways (PAG and RVM) that warrants further study.

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Microdialysis sampling for NAAG release in the PAG (a) and RVM (b) following inflammation. NAAG levels are expressed as a percent of the three baseline samples for each animal. ZJ43 (150 mg/kg, i.p.) prior to formalin treatment (Z-F) or saline prior to formalin (S-F). ZJ43 or saline was injected i.p. at 0 time followed by 50 μl of 5% formalin injected into the contralateral footpad at the 15 min time point. ZJ43 significantly (p < 0.001) increased NAAG levels in the PAG (a) and RVM (b). Samples were collected over 20 minute intervals. *p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 9: Microdialysis sampling for NAAG release in the PAG (a) and RVM (b) following inflammation. NAAG levels are expressed as a percent of the three baseline samples for each animal. ZJ43 (150 mg/kg, i.p.) prior to formalin treatment (Z-F) or saline prior to formalin (S-F). ZJ43 or saline was injected i.p. at 0 time followed by 50 μl of 5% formalin injected into the contralateral footpad at the 15 min time point. ZJ43 significantly (p < 0.001) increased NAAG levels in the PAG (a) and RVM (b). Samples were collected over 20 minute intervals. *p < 0.05; **p < 0.01; ***p < 0.001.

Mentions: Formalin injection had no effect on NAAG levels in PAG and RVM (Figure 9a, b). ZJ43 increased NAAG levels by ~20-fold. There was a significant difference in NAAG levels between groups in the 0–140 min PAG dialysate samples (p < 0.01), and an overall time × group interaction was observed for NAAG in PAG (F6, 36 = 7.711, p < 0.001). There was a significant difference in NAAG levels between groups in the 0-140 min RVM dialysate sample (p < 0.001) and an overall time × group interaction was observed for NAAG in RVM (F6, 60 = 24.368, p < 0.001).


NAAG peptidase inhibition in the periaqueductal gray and rostral ventromedial medulla reduces flinching in the formalin model of inflammation.

Yamada T, Zuo D, Yamamoto T, Olszewski RT, Bzdega T, Moffett JR, Neale JH - Mol Pain (2012)

Microdialysis sampling for NAAG release in the PAG (a) and RVM (b) following inflammation. NAAG levels are expressed as a percent of the three baseline samples for each animal. ZJ43 (150 mg/kg, i.p.) prior to formalin treatment (Z-F) or saline prior to formalin (S-F). ZJ43 or saline was injected i.p. at 0 time followed by 50 μl of 5% formalin injected into the contralateral footpad at the 15 min time point. ZJ43 significantly (p < 0.001) increased NAAG levels in the PAG (a) and RVM (b). Samples were collected over 20 minute intervals. *p < 0.05; **p < 0.01; ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539905&req=5

Figure 9: Microdialysis sampling for NAAG release in the PAG (a) and RVM (b) following inflammation. NAAG levels are expressed as a percent of the three baseline samples for each animal. ZJ43 (150 mg/kg, i.p.) prior to formalin treatment (Z-F) or saline prior to formalin (S-F). ZJ43 or saline was injected i.p. at 0 time followed by 50 μl of 5% formalin injected into the contralateral footpad at the 15 min time point. ZJ43 significantly (p < 0.001) increased NAAG levels in the PAG (a) and RVM (b). Samples were collected over 20 minute intervals. *p < 0.05; **p < 0.01; ***p < 0.001.
Mentions: Formalin injection had no effect on NAAG levels in PAG and RVM (Figure 9a, b). ZJ43 increased NAAG levels by ~20-fold. There was a significant difference in NAAG levels between groups in the 0–140 min PAG dialysate samples (p < 0.01), and an overall time × group interaction was observed for NAAG in PAG (F6, 36 = 7.711, p < 0.001). There was a significant difference in NAAG levels between groups in the 0-140 min RVM dialysate sample (p < 0.001) and an overall time × group interaction was observed for NAAG in RVM (F6, 60 = 24.368, p < 0.001).

Bottom Line: The group II mGluR antagonist LY341495 blocked these effects of ZJ43 on the PAG and RVM.NAAG peptidase inhibition in the PAG and RVM did not affect the thermal withdrawal response in the hot plate test.Footpad inflammation also induced a significant increase in glutamate release in the PAG.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Georgetown University, Washington, DC, USA.

ABSTRACT

Background: Metabotropic glutamate receptors (mGluRs) have been identified as significant analgesic targets. Systemic treatments with inhibitors of the enzymes that inactivate the peptide transmitter N-acetylaspartylglutamate (NAAG), an mGluR3 agonist, have an analgesia-like effect in rat models of inflammatory and neuropathic pain. The goal of this study was to begin defining locations within the central pain pathway at which NAAG activation of its receptor mediates this effect.

Results: NAAG immunoreactivity was found in neurons in two brain regions that mediate nociceptive processing, the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM). Microinjection of the NAAG peptidase inhibitor ZJ43 into the PAG contralateral, but not ipsilateral, to the formalin injected footpad reduced the rapid and slow phases of the nociceptive response in a dose-dependent manner. ZJ43 injected into the RVM also reduced the rapid and slow phase of the response. The group II mGluR antagonist LY341495 blocked these effects of ZJ43 on the PAG and RVM. NAAG peptidase inhibition in the PAG and RVM did not affect the thermal withdrawal response in the hot plate test. Footpad inflammation also induced a significant increase in glutamate release in the PAG. Systemic injection of ZJ43 increased NAAG levels in the PAG and RVM and blocked the inflammation-induced increase in glutamate release in the PAG.

Conclusion: These data demonstrate a behavioral and neurochemical role for NAAG in the PAG and RVM in regulating the spinal motor response to inflammation and that NAAG peptidase inhibition has potential as an approach to treating inflammatory pain via either the ascending (PAG) and/or the descending pain pathways (PAG and RVM) that warrants further study.

Show MeSH
Related in: MedlinePlus