Mecanismos e mediadores envolvidos na gênese e manutenção da hipernocicepção induzida pelo Chikungunya virus

Abstract

The main characteristic of chikungunya virus infection is chronic inflammatory polyarthralgia, which is associated with a high morbidity rate in the affected population. To date, the mediators and mechanisms associated with the development of chronic arthralgia in these patients are unknown and the available treatment measures are palliative and nonspecific. Here, using an experimental model, we studied some mechanisms and mediators involved in the genesis and maintenance of CHIKV-induced hypernociception. C57BL/6 wild type (WT) mice were infected with 106 PFU of CHIKV intraplantarly and several analyzes performed at pre-established times. The results showed that CHIKV infection induced prolonged mechanical hypernociception and thermal sensitivity. Intense tissue damage and increased levels of inflammatory mediators in the footpad, such as TNF and IL-6, were observed. An increase in the expression of CXCL-1, CCR5 and COX-2 on the 1st day post-infection and of TNF on the 7th and 14th days in the dorsal root ganglion (DRG) was also observed. Then, treatment with drugs of different therapeutic classes with analgesic potential was performed. Treatments with morphine and pregabalin (central action) reversed the hypernociceptive phenotype of mice in the acute and late phases of infection. On the other hand, treatments with dexamethasone or naproxen (anti-inflammatory action) were effective only in controlling CHIKV-induced acute hypernociception. Finally, we evaluated the role of the cytokine TNF in the induction and maintenance of hypernociception after CHIKV infection, using TNFRp55- / - mice or through the pharmacological inhibition of this molecule (etanercept). Our data showed that the absence of TNF improved disease parameters in the evaluated animals, since they showed less hypernociception, less tissue damage in the paw, less production of pro-inflammatory mediators and an increase in IL-10, a cytokine with anti-inflammatory activity, which opens perspectives for a potential therapeutic target. Thus, our data suggest that the genesis of CHIKVinduced hypernociception is dependent on local acute inflammation, but its maintenance seems to be associated with an inflammatory state in the DRG, more specifically with an increase in TNF expression in this tissue at later times.