Substance P receptor antagonists in the therapy of migraine

Clinical observations, the vascular component of migraine pain, its pulsating or throbbing pain character, have focused attention on the trigeminal innervation of pain-sensitive intracranial structures, such as the dura mater and large vessels. These intracranial structures are innervated by the ophthalmic branch of the trigeminal nerve, which is marked by the presence of vasoactive peptides, such as substance P and calcitonin gene-related peptide. Substance P is a mediator of the sterile inflammation of the dura mater, which has been considered to be the source of migraine pain. Modern antimigraine drugs, such as 5-HT(1B/D) agonists (triptans), block this dural neurogenic inflammation dose-dependently in an animal model but their vasoconstrictor effects have led to a search for non-vasoconstrictor approaches. One such approach has been substance P (neurokinin-1) antagonists. These are highly effective in animal models of dural inflammation and have no significant vasoconstrictive effect. However, several NK(1) antagonists failed to demonstrate any effect in acute migraine. Current clinical and experimental evidence therefore supports the view that NK(1) receptor antagonists may have no significant antimigraine properties.