The antiallodynic effects of intrathectlly applied IMT504 are related to modulation of glial/microglial responses and of the expression of inflammatory factors in rats with hindpaw inflammation

LEIGUARDA, C; POTILINSKI, C; TRIGOSSO-VANARIO H; MONTANER A; CONSTANDIL, L; BRUMOVSKY, P

Mar del Plata

Congreso; Reunión Conjunta SAIC-SAI-SAFIS; 2018

SAIC-SAI-SAFIS

Chronic immune diseases, pathogenic infection, or tissue injury are common medical conditions, often leading to the development of chronic inflammatory pain which is unfortunately difficult to treat and often unresponsive to conventional therapies. We recently showed that the oligodeoxynucleotide IMT504 has remarkable antiallodynic and anti-inflammatory effects upon systemic administration in rats undergoing unilateral hindpaw chronic inflammation. In this study, we addressed if IMT504 intrathecal (i.t.) delivery is capable of modulating mechanical allodynia and its underlying mechanisms of action in the spinal cord. Methods: Male Sprague-Dawley rats with complete Freund´s adjuvant (CFA)-induced unilateral hindpaw inflammation, received an acute i.t. injection of IMT504 (2µg/µl; 10 µl). C-reflex, wind-up and mechanical hyperalgesia were recorded during 72 h after injection. Spinal cords were processed for immunofluorescence or western blot analysis for markers of activated glia and microglia such as fibrillary acidic protein (GFAP) and integrin αM (OX42), toll-like receptor 4 (TLR-4) and NF-B p65 subunit. Results: Intrathecal IMT504 induced a clear reduction in mechanical hyperalgesia starting 1 h and lasting 48 h after administration, in association with parallel progressive reductions in C-reflex and wind-up responses. Furthermore, IMT504 significantly downregulated the expression of GFAP, OX42, TLR4 and NF-B. Conclusions: Altogether, we show that i.t. IMT504 efficiently eliminates inflammatory mechanical hyperalgesia for at least 24 h, in association with a depression in spinal sensitization and reductions in the activation of glia, microglia, and the NF-B and TLR-4 pathways. The exact mechanisms, by which these different events relate to explain the antihyperalgesic effects of IMT504, remain to be demonstrated. However, it could be hypothesized that the net effect of IMT504 are reductions in the synthesis of spinal pro-inflammatory mediators.