ROLE OF HISTAMINE IN RODENT ANTINOCICEPTION

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 dose-dependently antinociceptive in all three tests: 5 - 100 mug per rat in the paw pressure test, 5 - 50 mug per mouse in the abdominal constriction test and 50-100 mug per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 mug per rat in the paw pressure test and 0.1 - 1 mug per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3 The histamine H-3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40 mg kg-1) and i.c.v. (1.1 - 10 mug per rat and 3.4-10 mug per mouse) routes. 4 The histamine H-3 agonist, (R)-alpha-methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 mug per rat and 3 mug per mouse, or i.p. administration of 100 mg kg-1 in mice. In rats 20 mg kg-1, i.p., elicited hyperalgesia only 4 h after treatment. 5 Thioperamide-induced antinociception was completely prevented by pretreatment with a nonhyperalgesic i.p. dose of (R)-alpha-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 2 50 and 500 mg kg- 1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg-1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg-1, i.p. showed their maximum effect 2 h after treatment. 7 The histamine N-methyltransferase inhibitor, metoprine, elicited a long-lasting, dose-dependent antinociception in all three tests by both i.p. (10-30 mg kg-1) and i.c.v. (50-100 mug per rat) routes. 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)-alpha-fluoro-methylhistidine methylhistidine and with (R)-alpha-methylhistamine, respectively. L-Histidine antinociception was completely antagonized in all three tests by pretreatment with (S)-alpha-fluoromethylhistidine HCl (50 mg kg-1, i.p.) administered 2 h before L-histidine treatment. Similarly, metoprine antinociception was prevented by (R)-alpha-methylhistamine dihydrogenomaleate 20 mg kg-1, i.p. administered 15 min before metoprine. Both (S)-alpha-fluoromethylhistidine and (R)-alpha-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 H-3 antagonist, thioperamide is antinociceptive and the H-3 agonist, (R)-alpha-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 histaminergic system in the modulation of nociceptive stimuli is thus proposed.