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.

Figure 1.

Schematic representation of a CGRP receptor. A functional calcitonin gene–related peptide (CGRP) receptor requires 3 components. The calcitonin receptor–like receptor (CLR) which consists of 7 transmembrane domains, the receptor activity–modifying protein 1 (RAMP1), which confers specificity for binding with CGRP, and the RCP, which seems to be critical for signal transduction by promoting effective coupling to the G_s protein. G_s activates adenylyl cyclase (AC), which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA). Activated PKA can then regulate the activity of numerous intracellular processes, including the K⁺ channels, L-type Ca²⁺ channels, and cAMP response element binding (CREB) protein. Thus, the downstream effects of activation of the CGRP receptor include neuronal excitability, neurotransmitter release, nitric oxide (NO) production, and vasodilation. AMPA-R, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; ERK, extracellular receptor–activated kinase; NMDA-R, N-methyl-D-aspartate receptor; NOS, nitric oxide synthase; P, phosphorylation sites; RCP, receptor component protein.

Figure 2.

Schematic representation of pain pathways where calcitonin gene–related peptide (CGRP) is expressed. The tracts that contain nerve fibers expressing CGRP are shown in red, and the non-CGRP–expressing tracts are shown in blue. The central terminals of primary afferent fibers, some of which express CGRP, provide nociceptive inputs to second-order neurons of the spinal dorsal horns and the trigeminal nucleus caudalis (TNC). The second-order neurons project to supraspinal sites, particularly the parabrachial and thalamic nuclei, which then can send projections to cortical sites including the insula. Calcitonin gene-related peptide has been found in projections from parabrachial neurons to the posterior intralaminar thalamic complex and to the amygdala/striatal region, including the central nucleus of the amygdala (CeA). This region also receives inputs from the posterior intralaminar thalamic complex that express CGRP. In the periphery, stimulation of sensory nerve endings can elicit an axon reflex, releasing CGRP from adjacent axonal branches, thus propagating a neurogenic inflammation. DRG, dorsal root ganglion; TG, trigeminal ganglion.

Figure 3.

(A) Peripheral sensitization. Damage to tissue or nerves in the periphery results in the localized release of proinflammatory mediators such as bradykinin, histamine, chemokines and cytokines, nerve growth factor (NGF), adenosine triphosphate (ATP), prostaglandin E₂ (PGE₂) and creates acidic conditions (eg, H⁺). These substances can lower the activation threshold of peripheral nociceptors (ie, sensitization) or trigger action potentials, thus activating the nociceptors. Action potentials can cause release of excitatory transmitters from other branching terminals of the same axon (ie, axonal reflex), which elicits the release of inflammatory mediators from adjacent tissue and excites adjacent nerve endings, thus spreading the inflammatory response. Persistent activation of the nociceptors over time, along with the retrograde transport of NGF bound to its receptor, tyrosine kinase A (TrkA-NGF complex) causes transcriptional changes, resulting in the increased production of sodium channels, calcitonin gene–related peptide (CGRP), and substance P (SP). These changes result in enhanced excitability of the peripheral nerve and enhanced release of CGRP and SP, thus maintaining a state of peripheral sensitization. (B) Central sensitization. Increased outputs from primary afferent terminals increases the excitability of postsynaptic neurons, directly and through activation of secondary mechanisms. Activation of the N-methyl-D-aspartate (NMDA) receptor increases calcium inputs and sensitizes the neuron to further inputs, such that inputs that would normally be subthreshold are sufficient to generate an action potential. Calcitonin gene-related peptide receptor activation activates the G_s protein and elicits a number of signaling cascades that serve to enhance neuronal excitability. The downstream activation of protein kinase A (PKA) and protein kinase C (PKC) promotes phosphorylation of NMDA receptors and of calcium ion channels, increasing their activity. Protein kinase A can also increase nitric oxide synthase (NOS) activity, increasing the release of nitric oxide (NO). Nitric oxide along with glutamate and PGE₂ can act as retrograde transmitters increasing the output from primary afferent terminals. Moreover, the enhanced release of CGRP can also activate presynaptic CGRP receptors (CGRP-R) of adjacent terminals, further enhancing transmitter release. Over time, the increased phosphorylation of PKA and PKC can lead to transcriptional changes, such as the upregulation of receptors and ion channels, which increase the excitability of the second-order neuron, thus maintaining a state of central sensitization. AC, adenylyl cyclase; AMPA, amino-3-hydroxy-5-methylisoxazole-4-propionic acid; AMPA-R, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding; NMDA-R, N-methyl-D-aspartate receptor; pERK, phosphorylated extracellular signal–regulated kinase.

Figure 4.

Activation of trigeminal ganglion (TG) neurons, perhaps through the release of inflammatory mediators or in response to ischemia or a localized insult, results in the release of calcitonin gene–related peptide (CGRP) into the meningeal vasculature, which results in vasodilation and release of nitric oxide (NO), producing a neurogenic inflammation. Calcitonin gene-related peptide can also be secreted from the cell body within the TG, where it excites satellite glial cells, which in turn can release inflammatory mediators, thus resulting in cross-excitation and facilitation of an inflammatory loop. The CGRP receptors are also present on TG neurons that do not express CGRP. Thus, CGRP released in the meninges and TG can initiate and maintain peripheral sensitization. The release of CGRP and other excitatory neurotransmitters from the central terminals of the TG neurons in the trigeminal nucleus caudalis (TNC) can excite second-order neurons in the TNC, leading to central sensitization and the manifestation of hyperalgesia and allodynia. Calcitonin gene-related peptide can also sensitize primary afferent nerves by acting on the presynaptic CGRP receptors that are present on presynaptic terminals of primary afferents that do not express CGRP. *CGRP receptors are found on large-diameter TG neurons that do not express CGRP.