Pearls and pitfalls in experimental in vivo models of migraine: Dural trigeminovascular nociception

Background: Migraine is a disorder of the brain and is thought to involve activation of the trigeminovascular system, which includes the peripheral afferent projection to the nociceptive specific dura mater, as well as the central afferent projection to the trigeminal nucleus caudalis. Stimulation of the blood vessels of the dura mater produces pain in patients that is referred to the head similar to headache. Headache mechanisms: The likely reason for the pain is because the vascular structures of the dura mater, including the superior sagittal sinus and middle meningeal artery, are richly innervated by a plexus of largely unmyelinated sensory nerve fibers from the ophthalmic division of the trigeminal ganglion. Methodology: Stimulation of these nociceptive specific nerve fibers is painful and produces neuronal activation in the trigeminal nucleus caudalis. Preclinical models of headache have taken advantage of this primarily nociceptive pathway, and various animal models use dural trigeminovascular nociception to assay aspects of head pain. These assays measure responses at the level of the dural vasculature and the central trigeminal nucleus caudalis as a correlate of trigeminovascular activation thought to be involved in headache. Summary: This review will summarize the history of the development of models of dural trigeminovascular nociception, including intravital microscopy and laser Doppler flowmetry at the level of the vasculature, and electrophysiology and Fos techniques used to observe neuronal activation at the trigeminal nucleus caudalis. It will also describe some of pitfalls of these assays and developments for the future.