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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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Effect of microinjection of ZJ43 into the PAG. Saline or ZJ43 or ZJ43 with LY341495 were microinjected into the right PAG 10 min prior to formalin injection into the dorsal surface of the contralateral footpad (0 time). Formalin injection induced two phases of hindpaw flinching in the saline injected control rats (n = 6). Microinjection of 150 μg of ZJ43 (n = 7) reduced both phases of the formalin-induced pain response. Pre-treatment with 1 mg/kg of the group II mGluR antagonist LY341495 (i.p.) (n = 6) reversed the effect of ZJ43 on the rapid and slow responses. Ordinate: number of flinches per min; abscissa: time after drug administration (min). Data in this and subsequent figures are presented as the mean +/− S.E.M.
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Figure 2: Effect of microinjection of ZJ43 into the PAG. Saline or ZJ43 or ZJ43 with LY341495 were microinjected into the right PAG 10 min prior to formalin injection into the dorsal surface of the contralateral footpad (0 time). Formalin injection induced two phases of hindpaw flinching in the saline injected control rats (n = 6). Microinjection of 150 μg of ZJ43 (n = 7) reduced both phases of the formalin-induced pain response. Pre-treatment with 1 mg/kg of the group II mGluR antagonist LY341495 (i.p.) (n = 6) reversed the effect of ZJ43 on the rapid and slow responses. Ordinate: number of flinches per min; abscissa: time after drug administration (min). Data in this and subsequent figures are presented as the mean +/− S.E.M.

Mentions: Subcutaneous injection of formalin in the rat footpad produced a reliable biphasic display of flinching of the injected paw (Figure 2) consistent with our previous studies [6-8]. Microinjection of ZJ43 (150 μg) into the PAG contralateral to the inflamed footpad significantly decreased the number of flinches in both the early and late phase. These effects of ZJ43 were dose-dependent (Figure 3) and blocked by i.p. injection with the mGluR2/3 receptor antagonist LY341495 (Figure 4, p < 0.05). We previously found that systemic injection of this antagonist alone had no significant effect on the response in the formalin or sciatic nerve ligation tests although a ceiling affect in the former and floor effect in the latter could have precluded detecting a change in response [6-8,29]. To confirm the restricted distribution of the peptidase inhibitor from the injection site, particularly its close proximity to the aqueduct, ZJ43 was injected into the PAG ipsilateral to injected footpad. The ipsilateral injection response was significantly different from the response following contralateral PAG injection (Figure 5, Phase 1: ipsilateral, 36.4 ± 6.5; contralateral, 12.7 ± 2.1, p < 0.005; Phase 2: ipsilateral, 136 ± 21.5; contralateral, 79.4 ± 7.8, p < 0.05) and not significantly different from the response following saline injection into the contralateral PAG (Phase 1: 34.7 ± 5.5; Phase 2: 156 ± 15.6).


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)

Effect of microinjection of ZJ43 into the PAG. Saline or ZJ43 or ZJ43 with LY341495 were microinjected into the right PAG 10 min prior to formalin injection into the dorsal surface of the contralateral footpad (0 time). Formalin injection induced two phases of hindpaw flinching in the saline injected control rats (n = 6). Microinjection of 150 μg of ZJ43 (n = 7) reduced both phases of the formalin-induced pain response. Pre-treatment with 1 mg/kg of the group II mGluR antagonist LY341495 (i.p.) (n = 6) reversed the effect of ZJ43 on the rapid and slow responses. Ordinate: number of flinches per min; abscissa: time after drug administration (min). Data in this and subsequent figures are presented as the mean +/− S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Effect of microinjection of ZJ43 into the PAG. Saline or ZJ43 or ZJ43 with LY341495 were microinjected into the right PAG 10 min prior to formalin injection into the dorsal surface of the contralateral footpad (0 time). Formalin injection induced two phases of hindpaw flinching in the saline injected control rats (n = 6). Microinjection of 150 μg of ZJ43 (n = 7) reduced both phases of the formalin-induced pain response. Pre-treatment with 1 mg/kg of the group II mGluR antagonist LY341495 (i.p.) (n = 6) reversed the effect of ZJ43 on the rapid and slow responses. Ordinate: number of flinches per min; abscissa: time after drug administration (min). Data in this and subsequent figures are presented as the mean +/− S.E.M.
Mentions: Subcutaneous injection of formalin in the rat footpad produced a reliable biphasic display of flinching of the injected paw (Figure 2) consistent with our previous studies [6-8]. Microinjection of ZJ43 (150 μg) into the PAG contralateral to the inflamed footpad significantly decreased the number of flinches in both the early and late phase. These effects of ZJ43 were dose-dependent (Figure 3) and blocked by i.p. injection with the mGluR2/3 receptor antagonist LY341495 (Figure 4, p < 0.05). We previously found that systemic injection of this antagonist alone had no significant effect on the response in the formalin or sciatic nerve ligation tests although a ceiling affect in the former and floor effect in the latter could have precluded detecting a change in response [6-8,29]. To confirm the restricted distribution of the peptidase inhibitor from the injection site, particularly its close proximity to the aqueduct, ZJ43 was injected into the PAG ipsilateral to injected footpad. The ipsilateral injection response was significantly different from the response following contralateral PAG injection (Figure 5, Phase 1: ipsilateral, 36.4 ± 6.5; contralateral, 12.7 ± 2.1, p < 0.005; Phase 2: ipsilateral, 136 ± 21.5; contralateral, 79.4 ± 7.8, p < 0.05) and not significantly different from the response following saline injection into the contralateral PAG (Phase 1: 34.7 ± 5.5; Phase 2: 156 ± 15.6).

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