Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells

Luiz Fernando Ferrari; Celina Monteiro Lotufo; Dionéia Araldi; Marcos A Rodrigues; Larissa P Macedo; Sérgio H Ferreira; Carlos Amilcar Parada

doi:10.1073/pnas.1420601111

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Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells

Journal article

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Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells

Luiz Fernando Ferrari, Celina Monteiro Lotufo, Dionéia Araldi, Marcos A Rodrigues, Larissa P Macedo, Sérgio H Ferreira and Carlos Amilcar Parada

Proceedings of the National Academy of Sciences - PNAS, Vol.111(51), pp.18363-18368

12/23/2014

DOI: 10.1073/pnas.1420601111

PMID: 25489099

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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.

2-Amino-5-phosphonovalerate - pharmacology

Animals

Dinoprostone - metabolism

Ganglia, Spinal - cytology

Ganglia, Spinal - drug effects

Ganglia, Spinal - metabolism

Hyperalgesia - metabolism

Nociceptors - drug effects

Quinoxalines - pharmacology

Rats

Receptors, AMPA - metabolism

Receptors, N-Methyl-D-Aspartate - agonists

Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors

Receptors, N-Methyl-D-Aspartate - metabolism

Satellite Cells, Perineuronal - drug effects

Satellite Cells, Perineuronal - metabolism

Details

Title: Subtitle: Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells
Creators: Luiz Fernando Ferrari - Universidade de São Paulo
Celina Monteiro Lotufo
Dionéia Araldi - Universidade Estadual de Campinas (UNICAMP)
Marcos A Rodrigues - Universidade de São Paulo
Larissa P Macedo - Universidade Federal de Uberlândia
Sérgio H Ferreira - Universidade de São Paulo
Carlos Amilcar Parada - Universidade Estadual de Campinas (UNICAMP)
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.111(51), pp.18363-18368
DOI: 10.1073/pnas.1420601111
PMID: 25489099
ISSN: 0027-8424
eISSN: 1091-6490
Language: English
Date published: 12/23/2014
Academic Unit: Neuroscience and Pharmacology
Record Identifier: 9985177945902771

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