Finding New Drug Targets for the Treatment of Migraine Attacks

Abstract

No new preventive drugs specific to migraine have appeared for the last 20 years and existing acute therapies need improvement. Unfortunately, no animal models can predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy, the headache- or migraine-provoking property of naturally occurring signalling molecules can be tested in a human model. This model has predicted efficacy of nitric oxide synthase inhibition and calcitonin gene-related peptide receptor blockade. The pharmaceutical industry should pay more attention to human models, although methods are different from normal target validation.

The Extracranial Vascular Theory of Migraine—A Great Story Confirmed by the Facts

“…Conversely, there is a great deal of verifiable and unrefuted experimental, physiological, pharmacological, and clinical evidence to support Wolff's proposal that extracranial vasodilatation is a source of pain in migraine, albeit accompanied by lowered pain threshold, concurrent intramural vascular edema, and local sterile inflammation. 15,16,19,20,30,[34][35][36][39][40][41][42][43][44][45][48][49][50][51][52][53][54][60][61][62][63][64][65][66][67][71][72][73][74][75][76][77][78][79][80][81] Wolff's theory has stood the test of time.…”

“…Also pertinent, to date all migraine-provoking agents have had vasodilating properties. 53 Ergots.-Ergotamine tartrate has been used for acute migraine treatment for approximately 80 years. 36 In therapeutic doses it is a vasoconstrictor, and the drug potently constricts the terminal branches of the external carotid artery.…”

“…Impossible to ignore, then, is the fact that the single property shared by the most widely used anti‐migraine preparations—past, present, and (potentially) future—is their potent constriction of abnormally dilated extracranial arteries, simultaneously accompanied by the reduction or elimination of migraine pain. Also pertinent, to date all migraine‐provoking agents have had vasodilating properties 53 …”

Secondary headaches: secondary or still primary?

“…In compliance with the strong clinical similarity described above, GTN-triggered delayed headache is also associated with brain stem activation [12], supporting the hypothesis that the delayed headache after GTN-infusion is indeed a pure migraine attack. In recent years, the Copenhagen group investigated several other substances which showed a similar behaviour [13]. Otherwise there are also a number of substances, which also induce headache in migraineurs, however, without fulfilling the ICHD-II criteria for migraine as shown for carbachol [14].…”

The PACAP Receptor: A Novel Target for Migraine Treatment

“…1 Thus, clinical research to discover new specific drug targets for migraine is highly needed. 2 The origin of pain during migraine attacks is still not fully elucidated. Activation of peripheral trigeminal nociceptors in the perivascular space of cranial arteries probably generates input that leads to the experience of migraine pain.…”