Single-dose systemic administration of the oligodeoxynucleotide IMT504 results in long-lasting ameliorating effects on mechanical allodynia and edema in rats with chronic hindpaw inflammation

C. LEIGUARDA; M.J. VILLAR; A.D. MONTANER; M.F. CORONEL; P.R. BRUMOVSKY

Boston

Congreso; XVI World Congress on Pain; 2018

International Association for the Study of Pain

IMT504 is a synthetic ODN with the capacity to modulate cells of the immune system, such as lymphocyte B cells, plasmocytoid dendritic cells, CD56+ cells, mesenchymal stem cells (MSCs). We previously showed that the systemic administration of IMT504 prevents or ameliorates mechanical and thermal allodynia in rats with sciatic nerve crush. More recently, we demonstrated that multiple doses of IMT504 reduce mechanical allodynia and inflammation in rats undergoing chronic hindpaw inflammation. Moreover, we observed that early and late administration of IMT504 results in quick and long-lasting reductions in mechanical allodynia and hindpaw edema with a seemingly dose-dependent effect. Here we performed a series of experiments to determine if and at what concentration a single dose of IMT504 was capable of reducing mechanical allodynia and inflammation. Adult Sprague?Dawley male rats were used in all experiments. Unilateral hindpaw inflammation was induced by intraplantar injection of complete Freund´s adjuvant (CFA). Subcutaneous IMT504 was administered at concentrations of 2, 6 and 10 mg/kg, 7 days after induction of hindpaw inflammation. Control groups included vehicle-treated rats. Mechanical allodynia was tested using the von Frey test before any intervention (basal responses) and at different time-points after injury and IMT504 or vehicle administration, during 7 weeks. Hindpaw inflammation was evaluated by measurement of hindpaw dorsoventral thickness in awake rats. In addition, 7 weeks after injury, rats were perfused using Lana´s fixative and hindpaws dissected out for histological analysis of tissue sections stained with standard hematoxylin- eosin. Thickness of the dermis and the epidermis was measured and dermal inflammatory cell infiltration was evaluated and quantified. Hindpaw inflammation strongly decreased mechanical withdrawal thresholds, reaching allodynic levels 12h after injury. Vehicle-treated CFA rats remained allodynic throughout the entire tested time. In contrast, IMT504-treated CFA rats showed progressive recovery towards basal withdrawal thresholds 24h after initiation of treatment at single doses of 10 mg/kg and 6 mg/kg; in the following 48h, both groups showed normal withdrawal thresholds, which were maintained throughout the remaining survival time. In contrast, for rats receiving 2 mg/kg IMT504, it took 4 weeks to reach basal withdrawal thresholds. Hindpaw thickness was significantly reduced in rats treated with any of the three tested doses, lower levels reached between 3-5 days after initiation of treatment, and maintained throughout the entire experimental time; this was in sharp contrast with vehicle-treated rats, showing constantly increased dorsoventral thicknesses. Finally, vehicle-treated rats showed considerable dermal edema and inflammatory infiltration, whereas IMT504-treated rats exhibited a partial reduction in dermal edema and cell infiltration. The present study shows that administration of IMT504 in rats undergoing chronic hindpaw inflammation results in a strong reduction in mechanical allodynia and hindpaw edema. Importantly, these effects began taking place no more than 24 h after treatment initiation and were long-lasting. Analysis of dose-dependent effects suggests that in the rat, a single dose of 6 mg/kg IMT504 is highly efficient in its antiallodynic and anti-inflammatory effects. In addition, the persistence of a certain degree of edema and cell infiltration 6 weeks after initiation of treatment suggests that the antiallodynic effect of IMT504 is not entirely dependent on its anti-inflammatory effects. Altogether, while the mechanisms behind the modulation of pain and inflammation by IMT504 remain to be clarified, data suggests that its administration could be a promising therapeutic strategy against pain in patients suffering peripheral inflammation.