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

Abstract

The role of histamine H1, H2, H3 and H4 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 μmol), histamine‐trifluoromethyl‐toluidine (HTMT, H1 agonist, 0.002–2 μmol), clobenpropit (H4 agonist, H3 antagonist, 0.002–0.6 μmol) and to a lesser extent imetit (H3/H4 agonist, 0.03–3 μmol) all induced dose‐dependent scratching. Dimaprit (H2 agonist, 0.04–40 μmol) did not cause scratching. Mepyramine (H1 antagonist, 20 mg kg−1, i.p.) reduced scratching evoked by histamine and HTMT, but not that caused by H3 or H4 agonists. Thioperamide (H3/H4 antagonist, 20 mg kg−1, i.p.) reduced scratching induced by histamine, H3 and H4 agonists, but not that caused by HTMT. The non‐sedating H1 antagonist, terfenadine, also significantly reduced the scratching induced by the H1 agonist, HTMT. Cimetidine (H2 antagonist, 20 mg kg−1, i.p.) did not affect histamine‐induced scratching. These results indicate that activation of histamine H4 receptors causes itch in mice, in addition to the previously recognised role for H1 receptors in evoking itch. Histamine H4 receptor antagonists therefore merit investigation as antipruritic agents. British Journal of Pharmacology (2004) 142, 374–380. doi:

The role of histamine in neurogenic inflammation

“…Clobenproprit induced scratching responses in the mouse that were attenuated by pretreating the animals with the H4 receptor antagonist, JNJ7777120 (Dunford et al, 2007). Moreover, it has been reported that H4 receptor agonists are able to induce itch through a direct action on the peripheral nerves (Bell et al, 2004), and that H4 antagonists inhibit SP-induced itch, which has been found to be resistant to H1 receptor antagonists (Yamaura et al, 2009) Interestingly, in mice, blocking both the H1 receptors and the H4 receptors with a dual antagonist or a combination of drugs gave the maximum response; it almost completely abolished the itch response (Dunford et al, 2007).…”

“…Clobenproprit induced scratching responses in the mouse that were attenuated by pretreating the animals with the H4 receptor antagonist, JNJ7777120 (Dunford et al, 2007). Moreover, it has been reported that H4 receptor agonists are able to induce itch through a direct action on the peripheral nerves (Bell et al, 2004), and that H4 antagonists inhibit SP-induced itch, which has been found to be resistant to H1 receptor antagonists (Yamaura et al, 2009). More recently, Suwa et al (2011) demonstrated that JNJ7777120 (10 and 30 mg·kg −1 day), but not the histamine H1 receptor antagonist fexofenadine (30 mg·kg −1 day), reduces the scratching behaviour and ameliorates the skin lesions induced by repeated challenge with 2,4,6-trinitrochlorobenzene in hairless mice, in a dose-dependent manner (Suwa et al, 2011).…”

“…All of the histamine receptors are involved in mediating the histamine signal in neurons, but to different extents. The failure of cimetidine to suppress histamine-induced itch in Balb/C mice (Bell et al, 2004) indicates that H2 receptors are not involved in itch. The H1 receptor is the most extensively histamine receptor studied.…”

“…Clobenproprit induced scratching responses in the mouse that were attenuated by pretreating the animals with the H4 receptor antagonist, JNJ7777120 (Dunford et al, 2007). Moreover, it has been reported that H4 receptor agonists are able to induce itch through a direct action on the peripheral nerves (Bell et al, 2004), and that H4 antagonists inhibit SP-induced itch, which has been found to be resistant to H1 receptor antagonists (Yamaura et al, 2009) Interestingly, in mice, blocking both the H1 receptors and the H4 receptors with a dual antagonist or a combination of drugs gave the maximum response; it almost completely abolished the itch response (Dunford et al, 2007).In addition, other published data indicate that H1 and H4 receptors share a similar pathway, in that they stimulate neurons by increasing intracellular Ca 2+ levels (Shim and Oh, 2008). The histamine-induced increase in calcium levels is mediated through H1 receptors in rat cultured sensory neurons, and this effect is blocked by the PLC inhibitor U73122 (Nicolson et al, 2002).…”

TRP Channels and Pruritus

“…Among them, H 1 and H 4 are widely accepted as receptors responsible for itch sensation; however, quite interestingly, an H 3 receptor inverse agonist was also shown to induce scratching behavior in mice [54,62,63].…”