1 Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2 A wide range of i.c.v. doses of histamine 2HCI was studied. Relatively high doses were dosedependently antinociceptive in all three tests: 5-100 ,g per rat in the paw pressure test, 5-50 g per mouse in the abdominal constriction test and 50-1I 00 g per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 ftg per rat in the paw pressure test and 0.1-1 g per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3 The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40mgkg-') and i. 5 Thioperamide-induced antinociception was completely prevented by pretreatment with a nonhyperalgesic i.p. dose of (R)-a-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6 L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500mgkg-', i.p. were effective in the rat paw pressure test, and those of 500 and 1500mgkg'1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000mgkg'1, i.p. showed their maximum effect 2h after treatment. 8 To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-a-fluoromethylhistidine and with (R)-o-methylhistamine, respectively. L-Histidine antinociception was completely antagonized in all three tests by pretreatment with (S)-a-fluoromethylhistidine HCl (50 mg kg', i.p.) administered 2 h before L-histidine treatment. Similarly, metoprine antinociception was prevented by (R)-a-methylhistamine dihydrogenomaleate 20 mg kg-', i.p. administered 15 min before metoprine. Both (S)-a-fluoromethylhistidine and (R)-a-methylhistamine were used at doses which did not modify the nociceptive threshold when given alone. 9 The catabolism product, 1-methylhistamine, administered i.c.v. had no effect in either rat paw pressure or mouse abdominal constriction tests.10 These results indicate that the antinociceptive action of histamine may take place on the postsynaptic site, and that its hyperalgesic effect occurs with low doses acting on the presynaptic receptor. This hypothesis is supported by the fact that the H3 antagonist, thioperamide is antinociceptive and the H3 agonist, (R)-a-methylhistamine is hyperalgesic, probably modulating endogenous histamine release. L-Histidine and metoprine, which are both able to increase brain histamine levels, are also able to induce antinociception in mice and rats. Involvement of the histaminer...

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1 E ects of substances which are able to alter brain histamine levels and two histamine H 1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. 2 Imipramine (10 and 30 mg kg 71 , i.p.) and amitriptyline (5 and 15 mg kg 71 , i.p.) were used as positive controls. Their e ects were not a ected by pretreatment with the histamine H 3 receptor agonist, (R)-amethylhistamine, at a dose (10 mg kg 71 , i.p.) which did not modify the cumulative time of immobility. 3 The histamine H 3 receptor antagonist, thioperamide (2 ± 20 mg kg 71 , s.c.), showed an antidepressantlike e ect, with a maximum at the dose of 5 mg kg 71 , which was completely prevented by (R)-amethylhistamine. 4 The histamine-N-methyltransferase inhibitor, metoprine (2 ± 20 mg kg 71 , s.c.), was e ective with an ED 50 of 4.02 (2.71 ± 5.96) mg kg 71 ; its e ect was prevented by (R)-a-methylhistamine. 5 The histamine precursor, L-histidine (100 ± 1000 mg kg 71 , i.p.), dose-dependently decreased the time of immobility [ED 30 587 (499 ± 712) mg kg 71 ]. The e ect of 500 mg kg 71 L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-a-¯uoromethylhistidine (50 mg kg 71 , i.p.), administered 15 h before. 6 The highly selective histamine H 1 receptor agonist, 2-(3-tri¯uoromethylphenyl)histamine (0.3 ± 6.5 mg per mouse, i.c.v.), and the better known H 1 agonist, 2-thiazolylethylamine (0.1 ± 1 mg per mouse, i.c.v.), were both dose-dependently e ective in decreasing the time of immobility [ED 50 3.6 (1.53 ± 8.48) and 1.34 (0.084 ± 21.5) mg per mouse, respectively].7 None of the substances tested a ected mouse performance in the rota rod test at the doses used in the forced swim test. 8 It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like e ect, via activation of H 1 receptors.

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To investigate the influence of nitric oxide (NO) on the release of histamine and glutamate, the anterior hypothalamus of anaesthetized rats was superfused through a push-pull cannula either with artificial cerebrospinal fluid (CSF) or with various drugs dissolved in CSF. Hypothalamic superfusion with the NO-donating compounds linsidomine (200 mumol/l) or diethylamine-NO (DEANO, 100 mumol/l) led to a pronounced and sustained decrease in the histamine release rate, whereas the release rate of glutamate was enhanced. Superfusion with the inhibitor of NO synthase L-NG-nitro-L-arginine methyl ester (L-NAME, 200 mumol/l) increased the histamine release rate. The inhibitory effect of 200 mumol/l linsidomine was abolished by atropine (10 mumol/l). Superfusion with the glutamate receptor agonists glutamate (100 mumol/l) or N-methyl-D-aspartate (NMDA, 50 mumol/l) enhanced the histamine release rate. In the presence of linsidomine, the releasing effect of NMDA was not changed. These findings demonstrate that the release of histamine in the hypothalamus is diminished by endogenous NO. This effect of NO on histamine release seems to be due to enhanced release of acetylcholine from vicinal cholinergic neurons via stimulation of muscarinic acetylcholine receptors located presynaptically on histaminergic neurons. The NO-induced glutamate release seems to exert a subordinate stimulatory effect on histamine release. Finally, the inhibition of histamine release by NO is not due to blockade of NMDA receptors.

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To investigate whether H1 and H2 histamine receptors are implicated in the modulation of acetylcholine release by endogenous histamine, the ventral striatum of the conscious, freely moving rat was superfused by the push-pull superfusion technique with drugs and the release of acetylcholine was determined in the superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA, 50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect of triprolidine was not influenced either on simultaneous superfusion with 10 micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist) and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced acetylcholine release rate in the ventral striatum. Presuperfusion with alpha-fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of histamine, abolished the famotidine-induced release of acetylcholine. The releasing effect of famotidine was also abolished on simultaneous superfusion with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of acetylcholine elicited by famotidine was reversed to a decreased acetylcholine outflow when the striatum was superfused with the GABA(A) receptor antagonist bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2 agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the presence of bicuculline the release of acetylcholine by dimaprit was enhanced and prolonged. It seems possible that dimaprit and impromidine stimulate different subtypes of H2 receptors. The findings suggest that the release of acetylcholine in the striatum is modulated by neighbouring histaminergic neurons in a complex way. Stimulation of H1 histamine receptors, probably located on cholinergic neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors located on cholinergic or GABAergic neurons enhances the release of acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons exerts the opposite effect.

We have previously reported that the histaminergic system is involved in the control of pain perception, and that substances able to enhance histamine brain levels, such as the histamine-N-methyltransferase inhibitor, metoprine, induce antinociception. In the present study, in order to corroborate the idea of inducing antinociception by inhibiting histamine catabolism, the effects of a noncompetitive histamine-N-methyltransferase inhibitor. SKF 91488, were studied in rodents by means of tests inducing three different kinds of noxious stimuli: thermal (mouse hot plate), chemical (mouse abdominal constrictions) and mechanical (rat paw pressure). The ability to react to noxious stimuli was assessed by the rota-rod test. In addition, a competitive inhibitor of the histamine catabolism enzyme, BW 301 U, was studied in the hot plate test. SKF 91488 (30, 50 and 100 micrograms per animal i.c.v.) raised dose-dependently the pain threshold in all three tests. To verify whether SKF 91488-induced antinociception is due to inhibition of histamine-N-methyltransferase, (R)-alpha-methylhistamine, described to block histamine release and synthesis by stimulating the histamine H3-autoreceptor and activating the negative feed-back mechanism, was used. When administered at doses which do not alter the pain threshold per se, 0.5 microgram per rat i.c.v. or 10 mg kg-1 i.p. in mice, (R)-alpha-methylhistamine was able to antagonize significantly the antinociceptive effect induced by 30 micrograms per animal i.c.v. of SKF 91488. BW 301 U (30 and 100 mg kg-1 i.p.) showed a dose-dependent, long-lasting antinociception, which was also antagonized by pretreatment with (R)-alpha-methylhistamine. The present data show that the antinociceptive effect previously described for metoprine is not restricted to this molecule, but is also shared by other histamine-N-methyl-transferase inhibitors. This generalization provides further evidence to the importance of the histaminergic system in pain control mechanisms.