Pathophysiology

Migraine is a disabling neurological disorder that manifests as a debilitating headache associated with altered sensory perception (International Headache Society, 2013). Growing evidence suggests that migraine is a neurovascular disorder (Raddant & Russo, 2011), and while its exact cause is unclear, pathophysiological mechanisms have been proposed (Deen et al., 2017).

The neurological basis for migraine pain

The brain itself lacks pain receptors (nociceptors), however, they are present in the dura and pia of the meninges. Therefore, it is thought that development of a migraine headache involves the trigeminal system (Goadsby et al., 2002; Pietrobon & Striessnig, 2003; Messlinger, 2009) with migraine pain transmitted from the meninges through the trigeminal nerve (Moskowitz, 1993; Burgos-Vega et al., 2015).

Trigeminovascular input from the meningeal vessels passes through the trigeminal ganglion and synapses on second-order neurons in the brainstem before being relayed to the sensory cortex (Bigal et al., 2009).

Role of the trigeminovascular system in neurological migraine pain.

Figure 5: The neurological basis for migraine pain (Adapted from Burgos-Vega et al., 2015).

The trigeminal nerve innervates the meninges, cerebral blood vessels, and other areas of the head via three branches, the ophthalmic, maxillary and mandibular (Walker, 1990; Renton & Egbuniwe, 2015).

How does a migraine start?

Migraine pain starts with ‘abnormal’ activation of the trigeminovascular system (TGVS) (Raddant & Russo, 2011; Burgos-Vega et al., 2015; Russo, 2015). Activation of the TGVS causes release of various neuropeptides at the meninges that can induce neurogenic inflammation including (Raddant & Russi, 2011; Pietrobon & Moskowitz, 2013; Burgos-Vega et al, 2015; Russo, 2015):

  • calcitonin
  • CGRP
  • neurokinin A
  • substance P
 
 A feed-forward loop in the TGVS creates a state of hypersensitivity and sustained pain.

Figure 6: A feed-forward loop in the TGVS creates a state of hypersensitivity and sustained pain (Akerman et al., 2002; Capuano et al., 2009; Demarquay & Mauguière, 2016). TGN =Trigeminal nerve; TGVS = trigeminovascular system; TNC = trigeminal nucleus caudalis.

The role of CGRP in migraine pathophysiology

Although the underlying pathophysiology of migraine is mostly unknown, it is believed that the calcitonin gene-related peptide (CGRP) plays an important role (Deen et al., 2017). CGRP is a 37-amino acid sensory neurotransmitter that is widely distributed throughout both the central and the peripheral nervous system (Ho et al., 2010) and is the most abundant neuropeptide in the trigeminal system (Eftekhari et al., 2010).

CGRP plays a key role in several mechanisms of migraine pathology and pain perception, including (Russell et al., 2014):

  • vasodilation
  • neurogenic inflammation
  • mast cell degranulation
  • sensory signalling activation
  • peripheral sensitisation

During migraine attacks, serum levels of CGRP, which is a potent dilator of peripheral and cerebral blood vessels, are elevated (Goadsby et al., 1990; Edvinsson & Goadsby, 1998; Durham, 2006; Cernuda-Morollón et al., 2013). Further evidence reflecting the direct involvement of CGRP during attacks came from a double-blind crossover study which demonstrated that CGRP infusions induced migraine-like headache in patients with migraine (Lassen et al., 2002). Furthermore, the family of 5-HT1B and 5-HT1D agonists known as triptans, have been shown to reduce CGRP levels, concurrent with pain relief (Durham, 2006).

The CGRP receptor has three components and belongs to the family of G protein-coupled receptors (GPCRs) (Poyner et al., 2002; Russell et al., 2014):

  • calcitonin receptor-like receptor (CRLR)
  • receptor activity-modifying protein (RAMP1)
  • receptor component protein (RCP).

The calcitonin receptor family is large, and ligand specificity is determined by the combination of subunits (Poyner et al., 2002; Walker & Hay, 2013; Walker et al., 2015).

Cross-talk between calcitonin family ligands and receptors has been reported with CGRP binding the CGRP-receptor (CGRP-R) but also activating some amylin receptors at equal or higher potency than amylin (Poyner et al., 2002; Walker & Hay, 2013; Walker et al., 2015; Shi et al., 2016).

Calcitonin receptor family.

Figure 7: Calcitonin receptor family. CGRP = calcitonin gene-related peptide; CLR = calcitonin receptor-like receptor; RAMP = receptor activity-modifying protein. Footnotes: Figure adapted from Walker & Hay, 2013.

 

As a crucial role of CGRP in migraine pathophysiology has been demonstrated, agents designed to block its activity have recently been developed. These include small molecule and monoclonal antibodies (mAbs) targeting CGRP or its receptor with the goal of preventing migraine (Giamberardino et al., 2016; Deen et al., 2017).

The role of genetics in migraine

There is a population variation in migraine, 50% of cases are thought to be genetic in cause and 50% occur as a result of environmental factors (Tolner et al., 2015).

The genetic contribution to migraine is the result of a combination of single-nucleotide polymorphisms across many loci (Tolner et al., 2015). To date, genome-wide association studies have implicated 13 susceptibility genes, but the effect size of each individual polymorphism is small and interactions are complex (Ferrari et al., 2015).

Migraine susceptibility genes cluster into five domains.

Figure 8: Migraine susceptibility genes cluster into five domains (Ferrari et al., 2015).