The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Abstract

Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene–related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene–related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

“…The protein most associated with sensitization and activation of primary and secondary trigeminal neurons, and hence, the underlying pathology of migraine, is the neuropeptide CGRP (Bigal et al, 2013; Iyengar et al, 2017). CGRP is proposed to play a fundamental role in migraine since cerebrospinal fluid levels of CGRP are elevated during and between migraine attacks (van Dongen et al, 2017) and CGRP levels correlate with treatment response to anti-migraine drugs (Karsan and Goadsby, 2015).…”

“…In particular, members of the mitogen-activated protein kinase (MAPK) family mediate intracellular signaling cascades that promote neuron-glia interactions and maintain a hyperexcitable state of nociceptive neurons (Crown, 2012; Ji et al, 2009; Ji et al, 2013). The neuropeptide calcitonin gene-related peptide (CGRP), whose expression is regulated by MAPK and is strongly implicated in migraine pathology, can promote sensitization of primary and secondary trigeminal nociceptive neurons and activation of satellite glial cells in the ganglion and astrocytes and microglia in the spinal cord (Durham, 2016; Iyengar et al, 2017; Seybold, 2009). …”

Ryanodine‐ and CaMKII‐dependent release of endogenous CGRP induces an increase in acetylcholine quantal size in neuromuscular junctions of mice

“…It has been reported that CGRP is neurogenic and is released from motor nerve terminals in different tissues (Uchida et al., 1990; Sakaguchi et al., 1991; Macdonald et al., 2008; Iyengar et al. 2017). Thus, it looks more likely that ryanodine application to motor synapses initiates calcium release from presynaptic Ca 2+ ‐stores leading to secretion of endogenous CGRP from motor nerve terminals followed by an increase in MEPPs amplitude in motor synapses.…”

Novel Medications for the Treatment of Migraine

“…21 CGRP is a 37-amino acid neuropeptide, first described in 1983. [26][27][28][29][30] About 50% of the neurons in the trigeminal ganglion is CGRP-immunoreactive. 22 Neuropeptides are proteinaceous substances that are synthesized in the nucleus of the neuron and released from dense core vesicles.…”