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Open Access Research

Metabotropic glutamate receptor 5 contributes to inflammatory tongue pain via extracellular signal-regulated kinase signaling in the trigeminal spinal subnucleus caudalis and upper cervical spinal cord

Ming-Gang Liu12, Shingo Matsuura3, Masamichi Shinoda14*, Kuniya Honda15, Ikuko Suzuki1, Kazuo Shibuta1, Takaaki Tamagawa5, Ayano Katagiri16, Masaaki Kiyomoto7, Kinuyo Ohara3, Akihiko Furukawa5, Kentaro Urata8 and Koichi Iwata149

Author Affiliations

1 Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan

2 Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-746, Korea

3 Department of Endodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

4 Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo 101-8310, Japan

5 Department of Oral and Maxillofacial Surgery, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

6 Department of Psychosomatic Dentistry, Tokyo Medical and Dental University Graduate School, Tokyo, Japan

7 Department of Oral Diagnosis, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

8 Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, 1-8-13 Kanda-surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

9 Division of Applied System Neuroscience Advanced Medical Research Center, Nihon University Graduate School of Medical Science, 30-1 Ohyaguchi-Kamimachi Itabashi, Tokyo, 173-8610, Japan

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Journal of Neuroinflammation 2012, 9:258  doi:10.1186/1742-2094-9-258

Published: 27 November 2012

Abstract

Background

In the orofacial region, limited information is available concerning pathological tongue pain, such as inflammatory pain or neuropathic pain occurring in the tongue. Here, we tried for the first time to establish a novel animal model of inflammatory tongue pain in rats and to investigate the roles of metabotropic glutamate receptor 5 (mGluR5)-extracellular signal-regulated kinase (ERK) signaling in this process.

Methods

Complete Freund’s adjuvant (CFA) was submucosally injected into the tongue to induce the inflammatory pain phenotype that was confirmed by behavioral testing. Expression of phosphorylated ERK (pERK) and mGluR5 in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were detected with immunohistochemical staining and Western blotting. pERK inhibitor, a selective mGluR5 antagonist or agonist was continuously administered for 7 days via an intrathecal (i.t.) route. Local inflammatory responses were verified by tongue histology.

Results

Submucosal injection of CFA into the tongue produced a long-lasting mechanical allodynia and heat hyperalgesia at the inflamed site, concomitant with an increase in the pERK immunoreactivity in the Vc and C1-C2. The distribution of pERK-IR cells was laminar specific, ipsilaterally dominant, somatotopically relevant, and rostrocaudally restricted. Western blot analysis also showed an enhanced activation of ERK in the Vc and C1-C2 following CFA injection. Continuous i.t. administration of the pERK inhibitor and a selective mGluR5 antagonist significantly depressed the mechanical allodynia and heat hyperalgesia in the CFA-injected tongue. In addition, the number of pERK-IR cells in ipsilateral Vc and C1-C2 was also decreased by both drugs. Moreover, continuous i.t. administration of a selective mGluR5 agonist induced mechanical allodynia in naive rats.

Conclusions

The present study constructed a new animal model of inflammatory tongue pain in rodents, and demonstrated pivotal roles of the mGluR5-pERK signaling in the development of mechanical and heat hypersensitivity that evolved in the inflamed tongue. This tongue-inflamed model might be useful for future studies to further elucidate molecular and cellular mechanisms of pathological tongue pain such as burning mouth syndrome.

Keywords:
Metabotropic glutamate receptor 5; Extracellular signal-regulated kinase; Tongue pain; Inflammation; Trigeminal subnucleus caudalis; Upper cervical spinal cord