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

Molecular Pain

Joseph H Neale¹  John R Moffett²  Tomasz Bzdega⁴  Rafal T Olszewski⁴  Tatsuo Yamamoto³  Daiying Zuo⁵  Toshihiko Yamada³ 

[1] Department of Biology, Georgetown University, 37th and O Sts., NW, Washington, DC 20057, USA;Department of Anatomy, Physiology and Genetics, Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;Department of Anesthesiology, Kumamoto University, Kumamoto, Japan;Department of Biology, Georgetown University, Washington, DC, USA;Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China

关键词: Microdialysis;    Inflammatory pain;    LY341495;    mGluR3;    RVM;    PAG;    NAAG;    Analgesia;   

Others  :  863381
DOI  :  10.1186/1744-8069-8-67

 received in 2012-03-29, accepted in 2012-05-21,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Yamada et al.; licensee BioMed Central Ltd.

【 图 表 】

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