Dimaprit

Abstract: Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.

Abstract: New drugs selective for histamine H3-receptors can be used to establish that these receptors are involved in the feedback control of histamine synthesis and release, and to demonstrate their distribution in the brain and peripheral tissues These drugs provide new tools for affecting physiological and possibly pathological conditions in which histamine is involved

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.

Abstract: The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with 3H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl2 1.3 mmol/l (slices superfused with Ca2(+)-free medium containing K+ 20 mmol/l). Histamine slightly decreased the electrically evoked 3H overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC15 6.46). Under the latter condition, the evoked overflow was inhibited by the H3 receptor agonist R-(-)-alpha-methylhistamine and its S-(+) enantiomer (pIC15 7.36 and 5.09, respectively), but was not affected by the H2 receptor agonist dimaprit and the H1 receptor agonist 2-thiazolylethylamine (both at up to 32 mumols/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA2 8.37, 6.86 and 7.05, respectively), by the H2 receptor antagonist ranitidine (apparent pA2 4.27) and was not affected by the H1 receptor antagonist dimetindene (32 mumols/l). The inhibitory effect of R-(-)-alpha-methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked 3H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)