title: Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells.
abstract: The present study evaluated the role of N-methyl-D-aspartate receptors (NMDARs) expressed in the dorsal root ganglia (DRG) in the inflammatory sensitization of peripheral nociceptor terminals to mechanical stimulation. Injection of NMDA into the fifth lumbar (L5)-DRG induced hyperalgesia in the rat hind paw with a profile similar to that of intraplantar injection of prostaglandin E2 (PGE2), which was significantly attenuated by injection of the NMDAR antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) in the L5-DRG. Moreover, blockade of DRG AMPA receptors by the antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect in the PGE2-induced hyperalgesia in the paw, showing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG plays an important role in the peripheral inflammatory hyperalgesia. In following experiments we observed attenuation of PGE2-induced hyperalgesia in the paw by the knockdown of NMDAR subunits NR1, NR2B, NR2D, and NR3A with antisense-oligodeoxynucleotide treatment in the DRG. Also, in vitro experiments showed that the NMDA-induced sensitization of cultured DRG neurons depends on satellite cell activation and on those same NMDAR subunits, suggesting their importance for the PGE2-induced hyperalgesia. In addition, fluorescent calcium imaging experiments in cultures of DRG cells showed induction of calcium transients by glutamate or NMDA only in satellite cells, but not in neurons. Together, the present results suggest that the mechanical inflammatory nociceptor sensitization is dependent on glutamate release at the DRG and subsequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil;
authors.forename: Luiz Fernando
authors.initials: LF
authors.lastname: Ferrari
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil; Department of Physiological Science, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, 38400-902, Minas Gerais, Brazil; and.
authors.forename: Celina Monteiro
authors.initials: CM
authors.lastname: Lotufo
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, 13083-862, São Paulo, Brazil.
authors.forename: Dionéia
authors.initials: D
authors.lastname: Araldi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil;
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Rodrigues
authors.affiliation: Department of Physiological Science, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, 38400-902, Minas Gerais, Brazil; and.
authors.forename: Larissa P
authors.initials: LP
authors.lastname: Macedo
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil; shferrei@fmrp.usp.br caparada@unicamp.br.
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, 13083-862, São Paulo, Brazil shferrei@fmrp.usp.br caparada@unicamp.br.
authors.forename: Carlos Amilcar
authors.initials: CA
authors.lastname: Parada
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D027161:Satellite Cells, Perineuronal / Q000187:drug effects* / Q000378:metabolism
chemical_list: D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D015232:Dinoprostone
keywords: NMDA receptor; dorsal root ganglion; hyperalgesia; inflammatory pain; satellite cells