title: 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.
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.
authors.affiliation: Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Ming-Gang
authors.initials: MG
authors.lastname: Liu
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsuura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Shinoda
authors.forename: Kuniya
authors.initials: K
authors.lastname: Honda
authors.forename: Ikuko
authors.initials: I
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shibuta
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tamagawa
authors.forename: Ayano
authors.initials: A
authors.lastname: Katagiri
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kiyomoto
authors.forename: Kinuyo
authors.initials: K
authors.lastname: Ohara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Furukawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Urata
authors.forename: Koichi
authors.initials: K
authors.lastname: Iwata
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004576:Electromyography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000009:adverse effects; D007839:Functional Laterality; D005928:Glossitis / Q000139:chemically induced / Q000150:complications; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D010146:Pain / Q000209:etiology / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010648:Phenylacetates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012445:Sacrococcygeal Region / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism*; D014059:Tongue / Q000473:pathology; D014275:Trigeminal Caudal Nucleus / Q000378:metabolism*
chemical_list: C107349:2-chloro-5-hydroxyphenylglycine; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; C578937:Grm5 protein, rat; D010648:Phenylacetates; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D005620:Freund's Adjuvant; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005998:Glycine