Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301U, 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.

Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay

“…In addition to its antimalarial activity, AQ is also known as a potent inhibitor of the human histamine N-methyltransferase (HNMT) [31]. Other more potent inhibitors of HNMT such as SKF91488, tacrine, diphenhydramine and chlorpromazine [37-39] had no effect on PfPMT, suggesting that the interaction between PfPMT and AQ is unique.…”

Histaminergic Involvement in Neuropathic Pain Produced by Partial Ligation of the Sciatic Nerve in Rats

“…Concerning acute nociceptive pain, histamine H 1 receptors mediate somatic and visceral pain perception, 2 and stimulation of H 1 receptors has been reported to aggravate acute pain. 3,4 Histamine H 2 receptor antagonists and H 3 agonists also possess antinociceptive properties on acute nociceptive pain. 5,6 However, the role of the histaminergic system on neuropathic pain has not yet been clarified.…”

Membrane‐bound histamine N‐methyltransferase in mouse brain: possible role in the synaptic inactivation of neuronal histamine

“…For example, inhibition of brain HNMT has been shown to reverse amnesia (Malmberg‐Aiello et al . 2000), lower pain threshold (Malmberg‐Aiello et al . 1997) and decrease appetite (Lecklin et al .…”

“…Finally, if the histamine-methylating enzyme described presently is shown to be a new protein, then development of isoform-specific inhibitors of histamine metabolism could lead to important new classes of medications. For example, inhibition of brain HNMT has been shown to reverse amnesia (Malmberg-Aiello et al 2000), lower pain threshold (Malmberg-Aiello et al 1997) and decrease appetite (Lecklin et al 1995). As known inhibitors of HNMT have side-effects which limit therapeutic utility (Duch et al 1980), such new medications might be clinically useful.…”