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...

1 The ability to modify the pain threshold by the two M,-muscarinic agonists: AF-102B and by the specific M2-agonist arecaidine was examined in mice and rats by using three different noxious stimuli: chemical (writhing test), thermic (hot-plate test) and mechanical (paw pressure test).

The antinociceptive effects of systemically‐administered procaine, lignocaine and bupivacaine were examined in mice and rats by using the hot‐plate, writhing and tail flick tests. In both species all three local anaesthetics produced significant antinociception which was prevented by atropine (5 mg kg−1, i.p.) and by hemicholinium‐3 (1 μg per mouse, i.c.v.), but not by naloxone (3 mg kg−1, i.p.), α‐methyl‐p‐tyrosine (100 mg kg−1, s.c.), reserpine (2 mg kg−1, i.p.) or atropine methylbromide (5.5 mg kg−1, i.p.). Atropine (5 mg kg−1, i.p.) which totally antagonized oxotremorine (40 μg kg−1, s.c.) antinociception did not modify morphine (5 mg kg−1, s.c.) or baclofen (4 mg kg−1, s.c.) antinociception. On the other hand, hemicholinium, which antagonized local anaesthetic antinociception, did not prevent oxotremorine, morphine or baclofen antinociception. Intracerebroventricular injection in mice of procaine (200 μg), lignocaine (150 μg) and bupivacaine (25 μg), doses which were largely ineffective by parenteral routes, induced an antinociception whose intensity equalled that obtainable subcutaneously. Moreover, the i.c.v. injection of antinociceptive doses did not impair performance on the rota‐rod test. Concentrations below 10−10 m of procaine, lignocaine and bupivacaine did not evoke any response on the isolated longitudinal muscle strip of guinea‐pig ileum, or modify acetylcholine (ACh)‐induced contractions. On the other hand, they always increased electrically‐evoked twitches. The same concentrations of local anaesthetics which induced antinociception did not inhibit acetylcholinesterase (AChE) in vitro. On the basis of the above findings and the existing literature, a facilitation of cholinergic transmission by the local anaesthetics is postulated; this could be due to blockade of presynaptic muscarinic receptors.

1 The effect of atropine on the nociceptive system was examined in mice and rats by use of the hot-plate, writhing and tail-flick tests. 2 Atropine dose-dependently produced analgesia, no effect and hyperalgesia. Analgesia was observed in both species with doses ranging from 1 to lOOug kg-while hyperalgesia was obtained with 5mg kg-3 Atropine antinociception was prevented by pirenzepine (0.1 ug per mouse, i.c.v.), dicyclomine (1Omg kg-1, i.p.), atropine-methylbromide (0.5 pg per mouse, i.c.v.) and hemicholinium-3 (1 pg per mouse, i.c.v.). Naloxone (1mgkg-1, i.p.), a-methyl-p-tyrosine (100mgkg-1, s.c.) and reserpine (2mgkg-1, i.p.) were ineffective. 4 The site of atropine analgesia is in the CNS since it exerts its antinociceptive effect also when injected i.c.v. (1-10 ng per mouse). Moreover drugs which do not cross the blood-brain barrier, such as hemicholinium-3, pirenzepine and atropine methylbromide, were unable to antagonize atropine analgesia if administered i.p. 5 Atropine also in vitro, showed a biphasic action on electrically-evoked guinea-pig ileum contractions. Concentrations between 10-14 and 10-12 M increased electrically and nicotine-evoked contractions but did not affect acetylcholine-and oxotremorine-evoked contractions. Concentrations above 10-9M inhibited both electrically-and drug (acetylcholine, nicotine and oxotremorine)-evoked contractions while they were ineffective on unstimulated ileum. 6 On the basis of the above findings, amplification of cholinergic transmission by very low doses of atropine is postulated, through a selective blockade of presynaptic muscarinic autoreceptors, as the likely mechanism of action. 7 Atropine antinociception, unlike oxotremorine antinociception, was obtained without any impairment of mouse rota-rod performance. 8 The antagonism by pirenzepine and dicyclomine of oxotremorine and atropine antinociception suggests that M1 muscarinic receptor subtypes are responsible for cholinergic analgesia.

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