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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:

Voltage-gated sodium channels play an essential role in regulating the excitability of nociceptive primary afferent neurones. In particular the tetrodotoxin-sensitive (TTX-S) Na(V)1.7 and the tetrodotoxin-resistant (TTX-R) Na(V)1.8 and Na(V)1.9 channels have been suggested to play a role in inflammatory pain. Previous work has revealed acute administration of inflammatory mediators, such as Freund's complete adjuvant (FCA) or carrageenan caused an upregulation in the levels of Na(V)1.7 and Na(V)1.8 protein in DRG (dorsal root ganglia) tissue up to 4 days post-insult. In the present study, the expression of Na(V)1.7, Na(V)1.8 and Na(V)1.9 was examined over a 28 day timecourse during a rat model of FCA-induced chronic inflammatory joint pain. Using the retrograde tracer Fast Blue (FB) and specific Na(V)1.7, Na(V)1.8 and Na(V)1.9 sodium channel antibodies, immunohistochemical staining techniques were used to study sodium channel expression in a distinct population of L3-L5 knee joint afferent DRGs. In the ganglia, counts were made of positively labelled cells in the FB population. The results demonstrate that, following FCA injection, Na(V)1.9 expression is upregulated at days 14, 21 and 28 post-FCA, with Na(V)1.7 and Na(V)1.8 showing increased channel expression at days 14 and 28. These observations are accompanied by a unilateral joint hypersensitivity in the FCA-injected knee indicated by a behavioural shift in weight distribution measured using an incapacitance tester. The increased presence of these channels suggests that Na(V)1.7, Na(V)1.8 and Na(V)1.9 play a role, at least in part, in the maintenance of chronic inflammatory pain several weeks after the initial insult.

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1 We tested the hypothesis that functional P2X receptors are present on peripheral terminals of primary aerent articular nociceptors in the rat knee joint. Neural activity was recorded extracellularly from the medial articular nerve innervating the knee joint in rats anaesthetized with pentobarbitone. 2 The selective P2X receptor agonist, ab methylene ATP (abmeATP), and the endogenous ligand, ATP, caused a rapid short-lasting excitation of a sub-population of C and Ad nociceptive aerent nerves innervating normal knee joints when injected intra-arterially or intra-articularly, and this eect was antagonized by the non-selective P2 receptor antagonist PPADS. 3 Induction of a chronic (14 ± 21 days) unilateral in¯ammatory arthritis of the knee joint using locally injected Freund's adjuvant neither increased or decreased responsiveness of joint nociceptors to abmeATP or ATP. 4 Our results support the hypothesis that abmeATP-sensitive P2X receptors are expressed on peripheral nociceptive aerents in the rat knee joint suggesting that they may be involved in the initiation of nociception and pain.