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.