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 2HCl was studied. Relatively high doses were dose‐dependently antinociceptive in all three tests: 5–100 μg per rat in the paw pressure test, 5–50 μg per mouse in the abdominal constriction test and 50–100 μg per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 μg per rat in the paw pressure test and 0.1–1 μg 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 (10–40 mg kg−1) and i.c.v. (1.1–10 μg per rat and 3.4–10 μg per mouse) routes. 4 The histamine H3 agonist, (R)‐α‐methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 μg per rat and 3 μg per mouse, or i.p. administration of 100 mg kg−1in 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 non‐hyperalgesic i.p. dose of (R)‐α‐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 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 μg 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)‐α‐fluoro‐methylhistidine and with (R)‐α‐methylhistamine, respectively. l‐Histidine antinociception was completely antagoniz