Oligonucleotide IMT504 ameliorates mechanical and cold allodynia in rats with persistent neuropathic pain

CASADEI M; FIORE E; CORONEL F; LEIGUARDA C; GARCIA M; MAZZOLINI G; VILLAR M; MONTANER A; BRUMOVSKY P

Congreso; 17° Congreso Internacional de Dolor; 2018

IMT504, the prototype of a major class of immunomodulatory oligodeoxynucleotides (ODN), is able to modulate cells of the immune system, such as lymphocyte B cells, plasmocytoid dendritic cells, CD56+ cells and mesenchymal stem cells (MSCs). We previously showed that IMT504 prevents or ameliorates pain progression in rats with acute compression of the sciatic nerve. More recently, we also showed that chronic inflammation of the hindpaw in rats is prevented or ameliorated by multiple IMT504 doses in rats. Here we evaluated the effect of the systemic administration of a single dose of IMT504 on the development of mechanical and thermal allodynia in an experimental model of neuropathic pain, as well as the effect on mesenchymal stem cell mobilization.All procedures were performed on adult male Sprague-Dawley rats. The spared nerve injury (SNI) model was used to induce persistent neuropathic pain. In all experiments, the ODN IMT504, with sequence 5′-TCATCATT TTGTCATTTTGTCATT-3′ (developed by Immunotech SA, Argentina) was used. The rats were treated with IMT504 at a single dose of 6 mg/kg, administered 7 days post-SNI or with saline solution in the case of the vehicle-treated group. Mechanical and cold allodynia were measured for several days and weeks before and after treatment. For analysis of mesenchymal stem cell mobilization, the colony forming units-fibroblasts (CFU-F) assay was used. Bone marrow stromal cells (BMSC) were collected from femur and tibia from groups of rats sacrificed a different survival times (7, 8, 14 and 28 days) and cultured during 14 days, at which time CFU-F were observed and counted using an optical inverted microscope.All SNI rats exhibited marked increases in ipsilateral mechanical and cold allodynia, reaching allodynic levels, as early as 3 days after injury. Vehicle-treated rats remained allodynic throughout the entire tested period (6 weeks). In contrast, IMT504-treated SNI rats exhibited a progressive increase in mechanical withdrawal threshold and decrease in cold withdrawal frequency and cold score, starting one day after treatment initiation. The differences between IMT504- and vehicle-treated rats were statistically significant throughout the entire survival time analyzed (p< 0.0001). Moreover, while vehicle-treated rats remained allodynic for as much as 6 weeks after injury, IMT504-treated rats returned to basal mechanical and cold withdrawal levels within the first two weeks after treatment initiation and throughout the remaining tested period. Finally, comparison of the number of CFU-F derived from the bone marrow of IMT504- and vehicle-treated SNI rats revealed a decrease in the number of CFU-F in the IMT504-treated animals, starting one day after ODN administration and remaining reduced up to 28 days after injury (p