Antinociceptive activity of a 3(2H)-pyridazinone derivative in mice

The antinociceptive activity of a 3(2H)-pyridazinone derivative (18a) was investigated in mice. 18a administered at doses which did not change either motor coordination or locomotor activity was able to induce antinociceptive effects in four nociceptive tests, the hot plate test, the tail flick test, the writhing test, and the formalin test. In the hot plate and tail flick test, 18a-induced antinociception was observed both after intraperitoneal administration and after intracerebroventricular injection thus indicating 18a has a central site of action. The pretreatment with the opioid antagonist naloxone, the alpha2-antagonist yohimbine or the GABA(B) antagonist CGP 35348 did not change 18a-induced antinociception in the hot plate test and in the tail flick test. Pretreatment with nicotinic antagonist mecamylamine did not change 18a effects either. A reversion of the 18a effects was observed after pretreatment with the muscarinic antagonists atropine and pirenzepine. Binding experiments revealed that 18a binds to muscarinic receptors, suggesting that 18a antinociception is mediated by central muscarinic receptors. The above findings together with the lack of parasympathomimetic cholinergic side effects indicate useful clinical application for this compound.