14,100,101 In an extensive and influential review (see Table 2), it was suggested that neural activation releases vasoactive neurotransmitters from their afferent processes, which in turn provokes inflammatory changes in peripheral target tissues (in this instance, cerebral blood vessels).14 In addition, the data suggested that the release of substance

P (a vasodilator) from sensory fibers is important in mediating changes in vessel permeability. The finding in animals explains the unilateral distribution of migraine pain and could challenge the concept that the pain of vascular headache is due to dilating blood vessels. Finally, it Roscovitine chemical structure was suggested that there is a sterile inflammation of cranial blood vessels during migraine AUY-922 mouse attacks. Moskowitz concluded that “the relationship of trigeminovascular fibers to the pathogenesis of vascular head pain sheds light on possible mechanisms of migraine and other central nervous system conditions associated with headache and inflammation.”14 Studies along this line were carried out in the subsequent year and in 1987 a model of intracranial neurogenic inflammation was presented for use in rat.102 Electrical stimulation of the trigeminal ganglion resulted in ipsilateral

increase of tracers in the dura. In contrast, there was no extravasation in the brain.102 The neurogenic inflammation model was then used to demonstrate that ergot alkaloids, ergotamine, and dihydroergotamine, inhibited plasma extravasation and it was suggested “that the therapeutic effects of ergots in vascular headaches may result from peripheral blockade of small fiber (C or A-delta)-dependent neurogenic inflammation within the dura.103 Similar results

were obtained for indomethacin and aspirin104 and sumatriptan.105 It was suggested that the effect was mediated by 5-HT1B/1D receptors located on sensory trigeminal neurons.106,107 Up to now all effective, acute antimigraine drugs have indeed been proven to inhibit neurogenic protein extravasation (NPE).105,107,108 medchemexpress However, inhibition of NPE was not predictive for the antimigraine effect of all investigated new drug-groups. Thus, in 5 placebo-controlled clinical studies, drugs (eg, endothelin and NK-1 receptor antagonists) with potent inhibitory effect on dural NPE were not effective for acute migraine treatment.109-113 Because specific NPE inhibitors are without an effect in migraine, it has been difficult to find a pivotal role for dural neurogenic inflammation in migraine. It was shown, however, that valproate, which is effective in migraine prophylaxis, blocked plasma extravasion in the meninges.