Fig. 7
From: Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors
TPA023B reduces acute itch mainly through spinal α2GABAARs. a Antipruritic action of intrathecally injected TPA023B (0.3 mg kg−1) in wild-type mice. Chloroquine (100 µg) was injected intracutaneously into the left thigh. Time spent biting of the injected skin area (s min−1) and total number of scratching bouts counted during 0–10 min after pruritogen injection. P = 0.004, unpaired two-sided t-test, n = 7 and 6, for vehicle and TPA023B. b Antipruritic action of TPA023B (1 mg kg−1, p.o.) in hoxB8-α2−/− mice (n = 6 and 6, for vehicle and TPA023B), GABAAR α2fl/fl mice (n = 5 for both groups) and global α2GABAAR (H → R) point mutated mice (n = 6 and 5, for vehicle and TPA023B, respectively). Chloroquine (100 µg) was injected intracutaneously into the left thigh. Chloroquine-induced biting responses (total time spent biting the injected skin area) were virtually identical in all three genotypes (ANOVA followed by Bonferroni post-hoc test F(14,2) = 0.39, P = 1.0 for all comparisons). By contrast, biting responses in TPA023B (1 mg kg−1, p.o.) treated mice differed significantly between genotypes (ANOVA followed by Bonferroni post-hoc test F(2,13) = 10.6). +P ≤ 0.05; + +P ≤ 0.01. No significant difference (P = 0.45) was found between hoxB8-α2−/− mice and global α2 R/R mice indicating that at least the α2GABAAR-mediated component occurred through a spinal site. c Antipruritic actions of TPA023B (1 mg kg−1 p.o.) in sns-α2−/− mice lacking α2GABAARs specifically from small diameter nociceptive and pruritoceptive DRG neurons, n = 5 for all groups. Chloroquine (100 µg) was injected intracutaneously into the left thigh. TPA023B exerted similar antipruritic actions in α2fl/fl and sns-α2−/− mice (ANOVA followed by Bonferroni post-hoc test F(1,16) = 0.36) indicating that peripheral α2GABAARs do not contribute to the antipruritic actions of TPA023B. d, e Antipruritic effects of TPA023B (3 mg kg−1, p.o.) against itch evoked by intrathecally injected BNP (10 nmoles) (n = 7 per group) (d) or GRP (1 nmole) (n = 6 and 7 mice, for TPA023B and vehicle) (e). Unpaired two-sided t-tests. Error bars indicate s.e.m.
