The role of dorsal root ganglion-produced interleukin-1'beta' in development of inflammatory hyperalgesia

Author(s)

Dionéia Araldi

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2012-05-14

Examining board members

Carlos Amílcar Parada; Celina Monteiro da Cruz Lotufo; Yara Cury; Maria Cláudia Gonçalves de Oliveira; Adilson Roberto Cardoso

• Advisor: Carlos Amílcar Parada

Abstract

The release of Interleukin-1? (IL-1?) in the peripheral tissue stimulates the synthesis of Prostaglandins, specially, Prostaglandin-E2 (PGE2) that ultimately sensitize the peripheral afferent nociceptor inducing inflammatory hyperalgesia. We have recently demonstrated that IL-1? can directly activate IL-1R receptor of peripheral afferent nociceptor to induce release of PGE2 associated to development of hyperalgesia. IL-1? is also released in Dorsal Root Ganglion (DRG), however the role that IL-1? in DRG plays to development of inflammatory hyperalgesia is not yet elucidated. Therefore, the aim of this study was to investigate whether IL-1? released in the DRG and the activation of Interleukin-1 Receptor Type I (IL-1RI) is involved in the development of the inflammatory hyperalgesia. Administration of IL-1Ra (IL-1 receptor antagonist, 6 ?g) in the DRG of rats prevented the mechanical hyperalgesia (measured with Electronic von Frey) induced by intraplantar (i.pl) administration of Complete Freund's Adjuvant (CFA, 100 ?L), Carrageenan (Cg, 100 ?g) or IL- 1? (0.5 pg), but not by PGE2 (100 ng), measured 3 hours after their administrations. Also, peripheral i.pl administration of CFA or Cg induced an increase in IL-1? concentrations (measured by ELISA) in the DRG. Ganglionar (DRG-L5) treatment with oligonucleotides (ODN) antisense against IL-1RI (30 ?g/day for four days) reduced the expression of IL-1RI in the DRG-L5 and the mechanical hyperalgesia induced by CFA, Cg, and IL-1?, but not by PGE2 administered in peripheral tissue. We also verified the hypothesis that previous activation of neuronal IL-1RI in the peripheral tissue is important to the release of IL-1? in the DRG and to the subsequent PGE2-induced hyperalgesia. IL-1? (0.5 pg/paw) co-administrated with a sub-threshold dose of PGE2 (10 ng/paw), in hind paws treated with indomethacin, greatly induces hyperalgesia, which was prevented by pre-treatment with ODN antisense against IL-1RI or IL-1Ra (6 ?g) administrated in DRG. Also, IL-1Ra administrations reduced the COX-2 expression in DRG cells. To confirm IL-1RI activation in DRG cells, it was observed that IRAK-1 and IRAK-4 expression was increased in DRG neurons after administration of Cg or CFA in the peripheral tissue. These findings suggest that the development of inflammatory hyperalgesia depends on neuronal IL-RI activation in the peripheral tissue that, in turn, induces the release of IL- 1? in the DRG and subsequent COX-2 activation. These data provide new insights about the participation of DRG cells in the mechanisms underlying inflammatory hyperalgesia and reveal new interesting targets to control inflammatory hyperalgesia (AU)