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

Abstract

Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells Luiz Fernando Ferraria, Celina Monteiro Lotufoa,b, Dionéia Araldic, Marcos A. Rodriguesa, Larissa P. Macedob, Sérgio H. Ferreiraa,1, and Carlos Amilcar Paradac,1 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 termi- nals 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 thepaw, show- ing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG plays an impor- tant 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 satel- lite 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 sen- sitization is dependent on glutamate release at the DRG and sub- sequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG. Significance The present study provides evidence for a role of glutamate as a neuromodulator of the afferent nociceptive information. Our results show that the nociceptive impulse generated by an in- flammatory event in the peripheral tissue is regulated in the dorsal root ganglia (DRG) by a system that involves satellite glial cells and glutamatergic NMDA receptors. To our knowl- edge, this work is one of the first demonstrations of the in- volvement of glutamate in a modulatory process in the DRG, a site where there are no synapses, in addition to its classical role as a neurotransmitter. (AU)

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