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5-Hydroxytryptamine (5-HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5-HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5-HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5-HT-receptors in these preparations. In the aorta, 5-HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists. In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5-HT and methysergide produced prolonged biphasic responses. 5-HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5-HT and methysergide were also obtained in ear arteries from reserpine-treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline. Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery. In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5-HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5-HT and noradrenaline in rabbit aorta. In the ear artery the pA2 values for each of the four antagonists were virtually identical against 5-HT and noradrenaline and similar to those obtained on alpha-adrenoceptors in the aorta. We conclude that 5-HT and noradrenaline act directly at alpha-receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5-HT receptors. This insight into the distribution of 5-HT receptors and alpha-receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5-HT-receptors and a weak partial agonist at alpha-receptors. In the ear artery, methysergide was a partial agonist at alpha-receptors; it was only a weak antagonist of 5-HT because this preparation does not contain specific 5-HT-receptors. The cross-reactivity demonstrated throughout these experiments indicates that 5-HT-receptors and alpha-receptors, although distinct entities, have features in common. These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.
Apperley et al. (Fri,) studied this question.