The role of potassium channels in antihistamine analgesia.
The effect of the administration of pertussis toxin as well as modulators of different subtypes of K+ channels on the antinociception induced by the H1-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 microg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K(ATP) channel openers minoxidil and pinacidil potentiated the antinociception produced by the H1-antihistamines whereas the K(ATP) channel blocker gliquidone prevented the anti H1-induced analgesia. The Ca2+-gated K+ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H1-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K(ATP) and Ca2+-gated K+ channels, contrary to voltage-gated K+ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H1-antihistamines.
Galeotti
N
N
Department of Preclinical and Clinical Pharmacology, Viale G.B. Morgagni, Florence, Italy.
Ghelardini
C
C
Bartolini
A
A
D000818:Animals; D004155:Diphenhydramine / Q000494:pharmacology*; D004357:Drug Synergism; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011398:Promethazine / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D006634:Histamine H1 Antagonists; D016376:Oligonucleotides, Antisense; D015221:Potassium Channels; D010566:Virulence Factors, Bordetella; D004155:Diphenhydramine; D037342:Pertussis Toxin; D011398:Promethazine; D011738:Pyrilamine