Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301 U, in rodent antinociception.
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.
Malmberg-Aiello
P
P
Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy.
Lamberti
C
C
Ipponi
A
A
Hänninen
J
J
Ghelardini
C
C
Bartolini
A
A
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
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