Figure 6: TRPA1 activation by exemestane (EXE) and letrozole (LTZ) is enhanced by proinflammatory stimuli. | Nature Communications

Figure 6: TRPA1 activation by exemestane (EXE) and letrozole (LTZ) is enhanced by proinflammatory stimuli.

From: Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1

Figure 6

(a) Intraplantar (i.pl.; 10 μl) pretreatment (10 min) with the proteinase-activated receptor 2 (PAR2) activating peptide (AP; 1 μg), but not with the inactive PAR2 reverse peptide (RP; 1 μg), enhances nocifensor behaviour produced by EXE (1 nmol per 10 μl, i.pl.) or LTZ (10 nmol per 10 μl, i.pl.). AP and RP alone causes negligible nociception. The potentiated responses to EXE or LTZ are markedly attenuated by HC-030031 (HC; 100 mg kg−1, i.p.). (b) H2O2 (0.5 μmol per 10 μl, i.pl.) injection produces a transient nocifensor behaviour, lasting only 5 min (b, inset). Pretreatment (10 min before AI administration) with H2O2 (0.5 μmol per 10 μl, i.pl.) increases nocifensor behaviour produced by EXE (1 nmol per 10 μl, i.pl.) or LTZ (10 nmol per 10 μl, i.pl.). HC (100 mg kg−1, i.p.) inhibits the exaggerated responses to both EXE and LTZ. Dash (-) indicates the vehicle of HC. Points or columns are mean±s.e.m. of at least fiv mice for each group. §P<0.05 versus RP or AP or Veh H2O2; †P<0.05 versus Veh AP/EXE or Veh AP/LTZ or Veh H2O2/EXE or Veh H2O2/LTZ; *P<0.05 versus AP/EXE or AP/LTZ or H2O2/EXE or H2O2/LTZ; ANOVA followed by Bonferroni post hoc test. #P<0.05 versus Veh H2O2, Student’s t-test. (c) An active concentration of EXE or LTZ (both 100 μM) evokes inward currents in rat dorsal root ganglion (DRG) neurons, which also respond to allyl isothiocyanate (AITC; 100 μM) and capsaicin (CPS; 1 μM). Inward currents evoked by EXE, LTZ or AITC are inhibited in the presence of HC (50 μM), which does not affect CPS-evoked currents. Typical traces (d) and pooled data (e) showing that pre-exposure to AP (100 μM) or H2O2 (100 μM) exaggerates currents evoked by a subthreshold concentration of EXE and LTZ (both 20 μM). The inactive RP does not affect responses to EXE or LTZ (both 20 μM). The potentiated responses to EXE or LTZ are markedly attenuated by HC (50 μM). Veh is the vehicle of EXE, LTZ and AITC. Results are mean±s.e.m. of at least five independent experiments. §P<0.05 versus Veh, *P<0.05 versus EXE, LTZ or AITC and †P<0.05 versus EXE- or LTZ-AP and EXE- or LTZ-H2O2; ANOVA followed by Bonferroni post hoc test.

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