Blockade of the flare response to intradermal 5-hydroxytryptamine in man by MDL 72.222, a selective antagonist at neuronal 5-hydroxytryptamine receptors

Summary

MDL 72.222 is a potent and selective antagonist of excitatory neuronal 5-hydroxytryptamine (5-HT) receptors which has been shown to provide symptomatic benefit in migraine. In the present study, the effects of MDL 72.222 on the flare response to intradermal injection of 5-HT (10⁻⁵, 4×10⁻⁵ and 1.6×10⁻⁴ mol/l) have been examined in six healthy male volunteers using a double-blind, placebo-controlled, randomized, crossover design. The study consisted of two sessions separated by at least 5 days. Comparison of within and between day responses to 5-HT indicated good reproducibility. Significant attenuation of the flare response to 5-HT, 10⁻⁵ and 4×10⁻⁵ mol/l was observed following a slow (4 min) i.v. injection of MDL 72.222, 20 mg. No significant change was observed for the 1.6×10⁻⁴ mol/l dose. The investigator was able to guess with a high degree of accuracy the sequence of MDL 72.222 and placebo (100% correct) and the order of 5-HT dose administration (70% correct), providing further evidence of the reproducibility and sensitivity of the method. MDL 72.222 was well tolerated. Thus, a dose of MDL 72.222 previously shown to provide symptomatic relief in migraine attenuates the flare response to intradermal 5-HT in the human forearm. The observation strengthens the view that the beneficial effects of MDL 72.222 in migraine result from blockade of the sensory neuronal stimulant effects of 5-HT and implies a role for 5-HT in the pain production of the acute attack.