Involvement of T-type channels in the development of inflammation and related mechanical hypersensitivity: pharmacological evidence
First, we investigated the effect of inhibiting T-type channels inhibition with TTA-A2 a pharmacological blocker with a great selectivity for T-type channels on inflammation and related pain in two murine models of inflammation: the carrageenan and CFA models. In the carrageenan model, vehicle treated mice had significantly increased responses to the von Frey test, thereby demonstrating the presence of a mechanical allodynia (Figure 1A left ), hyperalgesia (Figure 1B left ) and edema (Figure 1C left ). TTA-A2 (1 mg/kg, p.o. ) quickly and strongly suppressed nociceptive behavior for a period of 1-2 hours (Figures 1A left and 1B left ) and reduced edema size (Figure 1C left ). Similarly, in the CFA model seven day after the model induction, acute treatment with TTA-A2 (1 mg/kg, p.o. ), resulted in a transient analgesic effect similar to that observed in the carrageenan model (Figures 1A middle and 1B middle ). However, no effect on edema size was observed (Figure 1C middle ). In contrast, chronic TTA-A2 administration (1 mg/kg, p.o. ) for one week after CFA model induction (day 7 to 14) resulted in a progressive analgesic effect reaching significance after 5 days (from day 11 to 14 post CFA). Moreover the analgesic effect was long lasting, as indicated by the daily pain threshold measured 6 hours after the TTA treatment, a time point exceeding the duration of TTA acute effect (Figures 1A right and 1B right ). Unlike to the acute TTA-A2 treatment, chronic treatment significantly reduced edema size, with the same kinetics as that obtained for the analgesic effect (Figure 1C right ). Moreover, IL-6 levels in edemas at D14 were lower in TTA-A2 treated mice than in the VEH control (VEH: 4209.65 ± 166.58 pg/ml vs TTA-A2: 1719.20 ± 133.2 pg/ml, p = 0.0019, Mann Whitney test). Taken together, these pharmacological data provide supporting evidence toward an involvement of T-type channels in inflammation and related pain.