Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice

Abstract

The role of histamine H(1), H(2), H(3) and H(4) receptors in acute itch induced by histamine was investigated in female BalbC mice. Scratching was induced by intradermal injections of pruritogen into the back of the neck and "itch" assessed by quantifying the scratching evoked. Histamine (0.03-80 micromol), histamine-trifluoromethyl-toluidine (HTMT, H(1) agonist, 0.002-2 micromol), clobenpropit (H(4) agonist, H(3) antagonist, 0.002-0.6 micromol) and to a lesser extent imetit (H(3)/H(4) agonist, 0.03-3 micromol) all induced dose-dependent scratching. Dimaprit (H(2) agonist, 0.04-40 micromol) did not cause scratching. Mepyramine (H(1) antagonist, 20 mg kg(-1), i.p.) reduced scratching evoked by histamine and HTMT, but not that caused by H(3) or H(4) agonists. Thioperamide (H(3)/H(4) antagonist, 20 mg kg(-1), i.p.) reduced scratching induced by histamine, H(3) and H(4) agonists, but not that caused by HTMT. The non-sedating H(1) antagonist, terfenadine, also significantly reduced the scratching induced by the H(1) agonist, HTMT. Cimetidine (H(2) antagonist, 20 mg kg(-1), i.p.) did not affect histamine-induced scratching. These results indicate that activation of histamine H(4) receptors causes itch in mice, in addition to the previously recognised role for H(1) receptors in evoking itch. Histamine H(4) receptor antagonists therefore merit investigation as antipruritic agents.

Figure 1

Pooled data for histamine-induced scratching in female BalbC mice during the 20-min postinjection period (n=4–8). Histamine caused dose-dependent scratching. Dashed line represents the mean level of scratching induced by PBS, which served as a control (5±1 bouts of scratching, n=12).

Figure 2

Pooled data illustrating scratching induced by (a) HTMT (H₁ receptor agonist, n=6), (b) clobenpropit (H₄ agonist, H₃ antagonist, n=10), (c) imetit (H₃/H₄ agonist, n=6) and (d) dimaprit (H₂ agonist, n=3) during the 20 min postinjection. HTMT, clobenpropit, and to a lesser extent imetit, caused dose-related scratching, whereas dimaprit had no effect (dashed line illustrates PBS-induced scratching).

Figure 3

(a) Mepyramine (20 mg kg⁻¹ i.p.) significantly reduced scratching induced by histamine (8 μmol, i.d.) in female BalbC mice, 30 min after treatment with the antagonist versus pretreatment value (^*P<0.05, Wilcoxon matched pairs test, n=6). (b) Saline vehicle did not significantly reduce scratching induced by histamine (P>0.05, Wilcoxon matched pairs test, n=5). (c) Mepyramine (20 mg kg⁻¹ i.p.) pretreated mice showed a significantly lower scratching response to HTMT (0.2 μmol i.d.) in comparison with vehicle-treated animals (^*P<0.05, Mann–Whitney test, n=6 in each group). Mepyramine at lower doses (1, 3 or 10 mg kg⁻¹) did not significantly reduce HTMT-induced scratching (P>0.05, Mann–Whitney test, n=6 in each group). (d) Terfenadine significantly reduced scratching induced by HTMT (0.2 μmol i.d.) in a dose-dependent manner (terfenadine 20 mg kg⁻¹ versus control, ^*P<0.05, Mann–Whitney test, n=6 in each group) (V=vehicle for antagonist. Dashed line illustrates PBS-induced scratching).

Figure 4

(a) Thioperamide (20 mg kg⁻¹ i.p.) significantly reduced scratching induced by histamine (3 μmol, ^*P<0.05, Wilcoxon matched pairs test, n=6). (b) Saline vehicle did not significantly reduce scratching induced by histamine (P>0.05, Wilcoxon matched pairs test, n=6). (c) Thioperamide (20 mg kg⁻¹ i.p.) pretreated mice showed a significantly lower scratching response to imetit (3 μmol, i.d.) in comparison with vehicle treated animals (^*P<0.05, Mann–Whitney test, n=5 in each group). Thioperamide at lower doses (1, 3 or 10 mg kg⁻¹) did not significantly reduce imetit-induced scratching (P>0.05, Mann–Whitney test, n=4 in each group) (V=vehicle for antagonist. Dashed line illustrates PBS-induced scratching).

Figure 5

Thioperamide (20 and 10 mg kg⁻¹ i.p.) pretreated mice showed a significantly lower scratching response to clobenpropit (0.06 μmol, i.d.) in comparison with vehicle-treated animals (^*P<0.05, Mann–Whitney test, n=6 in each group). Thioperamide at lower doses (1, or 3 mg kg⁻¹) did not significantly reduce imetitinduced scratching (P>0.05, Mann–Whitney test, n=6 in each group) (V=vehicle for antagonist. Dashed line illustrates PBS induced scratching).

Figure 6

(a) Thioperamide (20 mg kg⁻¹ i.p.) did not significantly reduce HTMT-induced scratching (0.2 μmol i.d.) in comparison to vehicle treated mice (P>0.05, Mann–Whitney test, n=6 in each group), whereas the H₁ antagonist, terfenadine (20 mg kg⁻¹ i.p.) did reduce HTMT-induced scratching (^*P<0.05, Mann–Whitney test, n=6 in each group). (b) Mepyramine and terfenadine, sedating and nonsedating H₁ receptor antagonists, respectively (20 mg kg⁻¹ i.p.) did not significantly reduce clobenpropit-induced scratching (0.06 μmol i.d.) in comparison to vehicle-treated mice (P>0.05, Mann–Whitney test, n=6 in each group), whereas the H_3/4 antagonist, thioperamide (20 mg kg⁻¹ i.p.) did reduce clobenpropit-induced scratching (^*P<0.05, Mann–Whitney test, n=6 in each group). Dashed line illustrates PBS-induced scratching.