Experimental migraine models and their relevance in migraine therapy.

Although the understanding of migraine pathophysiology is incomplete, it is now well accepted that this neurovascular syndrome is mainly due to a cranial vasodilation with activation of the trigeminal system. Several experimental migraine models, based on vascular and neuronal involvement, have been developed. Obviously, the migraine models do not entail all facets of this clinically heterogeneous disorder, but their contribution at several levels (molecular, in vitro, in vivo) has been crucial in the development of novel antimigraine drugs and in the understanding of migraine pathophysiology. One important vascular in vivo model, based on an assumption that migraine headache involves cranial vasodilation, determines porcine arteriovenous anastomotic blood flow. Other models utilize electrical stimulation of the trigeminal ganglion/nerve to study neurogenic dural inflammation, while the superior sagittal sinus stimulation model takes into account the transmission of trigeminal nociceptive input in the brainstem. More recently, the introduction of integrated models, namely electrical stimulation of the trigeminal ganglion or systemic administration of capsaicin, allows studying the activation of the trigeminal system and its effect on the cranial vasculature. Studies using in vitro models have contributed enormously during the preclinical stage to characterizing the receptors in cranial blood vessels and to studying the effects of several putative antimigraine agents. The aforementioned migraine models have advantages as well as some limitations. The present review is devoted to discussing various migraine models and their relevance to antimigraine therapy.

Lack of effect of the adenosine A1 receptor agonist, GR79236, on capsaicin-induced CGRP release in anaesthetized pigs.

Migraine is a common neurological disorder that is associated with an increase in plasma calcitonin gene-related peptide (CGRP) levels. CGRP, a potent vasodilator released from the activated trigeminal sensory nerves, dilates intracranial blood vessels and transmits vascular nociception. Hence, inhibition of trigeminal CGRP release may prevent neurotransmission and, thereby, ameliorate migraine headache. Therefore, the present study in anaesthetized pigs investigates the effects of a selective adenosine A(1) receptor agonist, GR79236 (3, 10 and 30 microg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on plasma CGRP release. Intracarotid (i.c.) infusion of capsaicin (10 microg/kg/min, i.c.) increased the total carotid blood flow and conductance as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently attenuated by GR79236. However, the increases in the plasma CGRP concentrations by capsaicin remained essentially unmodified after GR79236 treatment. The above results suggest that GR79236 may have an antimigraine potential due to its postjunctional effects (carotid vasoconstriction) rather than to prejunctional inhibition of trigeminal CGRP release.

Effects of sumatriptan on capsaicin-induced carotid haemodynamic changes and CGRP release in anaesthetized pigs.

It is suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Hence, inhibition of trigeminal CGRP release may prevent the above vasodilatation and, accordingly, abort migraine headache. Therefore, this study investigated the effects of sumatriptan (100 and 300 microg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on CGRP release. Intracarotid (i.c.) infusions of capsaicin (10 microg/kg/min, i.c.) increased total carotid, arteriovenous anastomotic and capillary conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. Except for some attenuation of arteriovenous anastomotic changes, the capsaicin-induced responses were not affected by sumatriptan. Moreover, i.c. infusions of capsaicin (0.3, 1, 3 and 10 microg/kg/min, i.c.) dose-dependently increased the jugular venous plasma concentrations of CGRP, which also remained unaffected by sumatriptan. The above results support the contention that the therapeutic action of sumatriptan is mainly due to cranial vasoconstriction rather than trigeminal (CGRP release) inhibition.