Abstract
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 301U, was studied in the hot plate test.
SKF 91488 (30, 50 and 100 μg 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)-α-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 μg per rat i.c.v. or 10 mg kg–1 i.p. in mice, (R)-α-methylhistamine was able to antagonize significantly the antinociceptive effect induced by 30 μg per animal i.c.v. of SKF 91488. BW 301U (30 and 100 mg kg–1 i.p.) showed a dose-dependent, long-lasting antinociception, which was also antagonized by pretreatment with (R)-α-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-methyltransferase inhibitors. This generalization provides further evidence to the importance of the histaminergic system in pain control mechanisms.
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Received: 23 July 1996 / Accepted: 1 November 1996
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Malmberg-Aiello, P., Lamberti, C., Ipponi, A. et al. Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301U, in rodent antinociception. Naunyn-Schmiedeberg's Arch Pharmacol 355, 354–360 (1997). https://doi.org/10.1007/PL00004954
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DOI: https://doi.org/10.1007/PL00004954