**4. Headache and Migraine**

Primary headaches (i.e., those that are not associated with another disorder) are one of the most common causes of disability worldwide. The various types of headache include migraine, tension, and trigeminal autonomic cephalalgia [100]. Migraine is a multifactorial and incapacitating neurovascular disorder characterized by recurrent attacks of severe, unilateral, and throbbing headache, which can be aggravated by routine physical activity and can last from several hours to several days [100]. Migraine attacks often involve not only head pain, but also several premonitory and postdromal symptoms that occur before the headache initiates and persist after the headache ends, respectively. These symptoms are diverse and may include hypersensitivity to light, sound, smell, fatigue, neck stiffness, yawning, mood change, nausea, vomiting, cutaneous allodynia, and transient visual disturbances termed aura [101–104]. Migraine attacks can be triggered by many internal and external stimuli such as stress, hormonal fluctuations, sleep disturbances, skipping meals, weather changes, and ingestion of alcoholic beverage or certain types of food [105,106]. This multifactorial origin, as well as the variety of symptoms, have complicated identification of the underlying mechanisms of migraines. Although the events that trigger migraines remain unknown, the pain phase of migraine headaches is thought to involve activation and sensitization of primary afferent nociceptors that innervate the dural and meningeal vasculature. Indeed, the trigeminovascular system (TGVS) is a key component in pain initiation and transmission in migraine. Specifically, perivascular TG nerve endings are known to release CGRP, which induces vasodilation of cranial blood vessels and degranulation of meningeal mast cells, leading to neurogenic inflammation [107,108]. Interestingly, recent evidence indicated that a variety of ion channels, including TRP channels, make important contributions to migraine physiopathology (Figure 2 and Table 1). Several recent reviews discussed involvement of TRP channels in migraine, confirming significant interest in these channels as molecular targets for treatment of migraine [109–111]. In the following sections, we will discuss recent findings regarding TRP channels in migraine.

**Figure 2.** Transient receptor potential (TRP) channels in the trigeminovascular system and migraine development. Migraine triggering events remain unknown and may be a central or peripheral process. The precise order of events contributing to migraine pain is also debated. It is generally admitted that activation and sensitization of primary afferent nociceptors that innervate the dural and meningeal vasculature trigger both calcitonin gene-related peptide (CGRP)-induced vasodilatation and neurogenic inflammation. Pain signals pass through the trigeminal nucleus caudalis, which relays signals to higher order neurons in the thalamus and cortex (green arrows). A trigemino–parasympathetic or trigeminal autonomic reflex arc passes through the sphenopalatine ganglion and is responsible for migraine pain by mediating neurogenic inflammation (blue arrow). Central and peripheral sensitization (pink arrows) may contribute to maintenance of pain signals and predispose to future migraine attacks. Transient receptor potential (TRP) vanilloid 1 (TRPV1) and anoctamin 1 (ANO1) might be involved in initiation, nociception, and sensitization processes of migraine. TRP ankyrin 1 (TRPA1) might be more relevant in the initiation phase. There are few studies available on TRPV4 and TRP melastatin 8 (TRPM8), yet these receptors might be important in pain signal transmission or neurogenic inflammation.

**Table 1.** Roles of transient receptor potential (TRP) channels in migraine and their potential as therapeutic targets. RNS: reactive nitrogen species, ROS: reactive oxygen species, TRPA1: transient receptor potential ankyrin 1, TRPM8: transient receptor potential melastatin 8, TRPV1: transient receptor potential vanilloid 1, TRPV4: transient receptor potential vanilloid 4.

