Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (9), p.3603-3608
• Main Authors: Araldi, Dionéia, Ferrari, Luiz Fernando, Lotufo, Celina Monteiro, Vieira, André Schwambach, Athié, Maria Carolina Pedro, Figueiredo, Jozi Godoy, Duarte, Djane Braz, Tambeli, Claudia Herrera, Ferreira, Sérgio Henrique, Parada, Carlos Amilcar
• Format: Article
• Language: English
• Subjects: Afferent neurons; Animals; Biological Sciences; Biosynthesis; Carrageenan - pharmacology; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase inhibitors; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - pharmacology; Drug use; Enzyme Activation - drug effects; Ganglia, Spinal - drug effects; Ganglia, Spinal - enzymology; Ganglia, Spinal - pathology; Gene expression; Gene Knockdown Techniques; Hyperalgesia; Hyperalgesia - complications; Hyperalgesia - enzymology; Hyperalgesia - pathology; Indomethacin - administration & dosage; Indomethacin - pharmacology; Inflammation - complications; Inflammation - enzymology; Inflammation - pathology; Interleukin-1beta - pharmacology; Lipids; Lumbar Vertebrae - drug effects; Lumbar Vertebrae - pathology; Male; Membrane Proteins - metabolism; Neurochemistry; Neurology; Neurons; Pain; Prostaglandins; Protein isoforms; Protein Kinase C-epsilon - metabolism; Protein Transport - drug effects; Rats; Rats, Wistar; Receptors; Receptors, Prostaglandin E - antagonists & inhibitors; Receptors, Prostaglandin E - metabolism; Rodents; Salicylates; Spinal cord; TRPV Cation Channels - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1220668110

It is well established that dorsal root ganglion (DRG) cells synthesize prostaglandin. However, the role that prostaglandin plays in the inflammatory hyperalgesia of peripheral tissue has not been established. Recently, we have successfully established a technique to inject drugs (3 μL) directly into the L5-DRG of rats, allowing in vivo identification of the role that DRG cell-derived COX-1 and COX-2 play in the development of inflammatory hyperalgesia of peripheral tissue. IL-1β (0.5 pg) or carrageenan (100 ng) was administered in the L5-peripheral field of rat hindpaw and mechanical hyperalgesia was evaluated after 3 h. Administration of a nonselective COX inhibitor (indomethacin), selective COX-1 (valeryl salicylate), or selective COX-2 (SC-236) inhibitors into the L5-DRG prevented the hyperalgesia induced by IL-1β. Similarly, oligodeoxynucleotide-antisense against COX-1 or COX-2, but not oligodeoxynucleotide-mismatch, decreased their respective expressions in the L5-DRG and prevented the hyperalgesia induced by IL-1β in the hindpaw. Immunofluorescence analysis demonstrated that the amount of COX-1 and COX-2, constitutively expressed in TRPV-1 ⁺ cells of the DRG, significantly increased after carrageenan or IL-1β administration. In addition, indomethacin administered into the L5-DRG prevented the increase of PKCε expression in DRG membrane cells induced by carrageenan. Finally, the administration of EP1/EP2 (7.5 ng) or EP4 (10 µg) receptor antagonists into L5-DRG prevented the hyperalgesia induced by IL-1β in the hindpaw. In conclusion, the results of this study suggest that the inflammatory hyperalgesia in peripheral tissue depends on activation of COX-1 and COX-2 in C-fibers, which contribute to the induction and maintenance of sensitization of primary sensory neurons.