CGRP and the Trigeminal System in Migraine

Abstract

Objective: The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene-related peptide (CGRP) within the context of the trigeminovascular system.

Background: Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system.

Design: This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points.

Results: The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second-order neurons. A shift in central sensitization from activity-dependent to activity-independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder.

Conclusions: CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.

Keywords: calcitonin gene-related peptide; migraine; nitric oxide; sensitization; trigeminal system.

Figure 1

Some event occurring centrally, such as oscillations in hypothalamic activity and/or increased cortical excitability, can activate the trigeminovascular system to cause release of CGRP from CGRP‐ergic trigeminal afferent C‐fibers. In addition, CSD, regardless of its possible role in migraine pathogenesis, can cause liberation of extracellular potassium (K⁺) and hydrogen (H⁺) ions as well as proinflammatory substances from meningeal glia cells and nerve terminals. These substances can activate trigeminal nerve endings, resulting in the release of CGRP. Thus, whether the initiating event is central or peripheral, CGRP can act on its receptors on neighboring terminals of trigeminal afferent myelinated Aδ fibers, leading to sensitization of these sensory neurons. Moreover, acting on endothelial CGRP receptors, released CGRP can produce direct vasodilation and activate signaling cascades resulting in activation of eNOS and NO production. NO causes vasodilation and diffuses to the trigeminal nerve terminal, where it can enhance the further release of CGRP. Calcitonin gene‐related peptide (CGRP); endothelial nitric oxide synthase (eNOS); nitric oxide (NO).

Figure 2

Trigeminal CGRP‐ergic C‐fiber nociceptive neurons can secrete CGRP in the trigeminal ganglion, which can diffuse to satellite cells, evoking the release of NO. NO can diffuse back to the TG neuron, as well as to adjacent non‐CGRP neurons, thereby enhancing their activity. Moreover, CGRP can act directly on adjacent non‐CGRP Aδ sensory neuronal cell bodies that express the CGRP receptor, resulting in their sensitization. Calcitonin gene‐related peptide (CGRP); CGRP receptor (CGRP‐R); nitric oxide (NO); neuronal nitric oxide synthase (nNOS); trigeminal ganglion (TG).

Figure 3

CGRP released from the central terminals of unmyelinated nociceptive C‐fiber TG neurons can activate the CGRP receptors of the second‐order neurons, and elicit production of NO via nNOS. NO acts as a retrograde neuromodulator and enhances the activity of both the CGRP and non‐CGRP nerve terminals synapsing with the second‐order neuron, resulting in enhanced transmitter release. CGRP released from the TG neuron can also activate astrocytes, eliciting the release of NO and other inflammatory mediators, and act on receptors on the terminals of neighboring Aδ neurons that express the CGRP receptor, leading to their sensitization. Moreover, the release of excitatory transmitters such as glutamate from second‐order neurons and astrocytes results in activation of NMDA and AMPA receptors on second‐order neurons, on primary afferent nerve terminals, and on astrocytes to further promote release of excitatory substances, thus further enhancing the activity of the second‐order neuron and leading to a state of central sensitization. α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R); calcitonin gene‐related peptide (CGRP); N‐methyl‐D‐aspartate (NMDA); nitric oxide (NO); neuronal nitric oxide synthase (nNOS); trigeminal ganglion (TG).