title: Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301 U, in rodent antinociception.
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 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.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Malmberg-Aiello
authors.forename: C
authors.initials: C
authors.lastname: Lamberti
authors.forename: A
authors.initials: A
authors.lastname: Ipponi
authors.forename: J
authors.initials: J
authors.lastname: Hänninen
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: A
authors.initials: A
authors.lastname: Bartolini
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017259:Dimaprit / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D007276:Injections, Intraventricular; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D017442:Histamine Agonists; D008761:Methylhistamines; D011743:Pyrimidines; C024535:SK&F 91488; C069357:alpha-methylhistamine; D006637:Histamine N-Methyltransferase; C024530:piritrexim; D017259:Dimaprit