title: Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain.
abstract: Metabotropic glutamate receptor 5 (mGluR5) is an excitatory G-protein-coupled receptor (GPCR) present in the spinal cord dorsal horn (SCDH) where it has a well-established role in pain. In addition to its traditional location on the cytoplasmic membrane, recent evidence shows that these receptors are present intracellularly on the nuclear membrane in the spinal cord dorsal horn and are implicated in neuropathic pain. Nuclear mGluR5 is a functional receptor that binds glutamate entering the cell through the neuronal glutamate transporter (GT) EAAT3 and activates transcription factor c-fos, whereas plasma membrane mGluR5 is responsible for c-jun activation. Here, we extend these findings to a model of inflammatory pain using complete Freund's adjuvant (CFA) and show that nuclear mGluR5 is also upregulated in the spinal cord dorsal horn following inflammation. We also show that pretreatment with an excitatory amino acid transporter (EAAT) inhibitor attenuates pain and decreases Fos, but not Jun, expression in complete Freund's adjuvant rats. In contrast, selective glial glutamate transporter inhibitors are pronociceptive and increase spinal glutamate concentrations. Additionally, we found that permeable mGluR5 antagonists are more effective at attenuating pain and Fos expression than nonpermeable group I mGluR antagonists. Taken together, these results suggest that under inflammatory conditions, intracellular mGluR5 is actively involved in the relay of nociceptive information in the spinal cord.
authors.affiliation: Alan Edwards Centre for Research on Pain, Department of Anesthesia, McGill University, Montreal, QC, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vincent
authors.forename: Shu Fan
authors.initials: SF
authors.lastname: Wang
authors.forename: André
authors.initials: A
authors.lastname: Laferrière
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Coderre
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology; D004195:Disease Models, Animal; D050581:Excitatory Amino Acid Transporter 4 / Q000378:metabolism; D005620:Freund's Adjuvant / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D056284:Histone Deacetylase 1 / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D042541:Intracellular Space / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010146:Pain / Q000209:etiology / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D015820:Cadherins; D003505:Cyclodextrins; D050581:Excitatory Amino Acid Transporter 4; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D064529:Receptor, Metabotropic Glutamate 5; D018698:Glutamic Acid; D005620:Freund's Adjuvant; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1