The role of chemosensitive afferent nerves and TRP ion channels in the pathomechanism of headaches

The involvement of trigeminovascular afferent nerves in the pathomechanism of primary headaches is well established, but a pivotal role of a particular class of primary sensory neurons has not been advocated. This review focuses on the evidence that supports the critical involvement of transient receptor potential (TRP) channels in the pathophysiology of primary headaches, in particular, migraine. Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 receptors sensitive to vanilloids and other irritants are localized on chemosensitive afferent nerves, and they are involved in meningeal nociceptive and vascular responses involving neurogenic dural vasodilatation and plasma extravasation. The concept of the trigeminal nocisensor complex is put forward which involves the trigeminal chemosensitive afferent fibers/neurons equipped with specific nocisensor molecules, the elements of the meningeal microcirculatory system, and the dural mast cells. It is suggested that the activation level of this complex may explain some of the specific features of migraine headache. Pharmacological modulation of TRP channel function may offer a novel approach to the management of head pain, in particular, migraine.