Role of calcitonin gene-related peptide and brain natriuretic peptide to modulate the excitability state of trigeminal neurons: relevance to migraine pathology and treatment

Figures & data

Table 1 Current CGRP antagonists/antibodies in clinical trial for migraine therapy

Code name	Type	Indication	Administration route	Clinical phase	References
BIBN4096BS (olcegepant)	CGRP receptor antagonist	Acute treatment	intravenous	Phase II	75,104–106
BI 44370 TA	CGRP receptor antagonist	Acute treatment	Oral	Phase II	107
BMS-927711	CGRP receptor antagonist	Acute treatment	Oral	Phase II	108,109
MK-1602	CGRP receptor antagonist	Acute treatment	Oral	Phase II	In progress (NCT01613248)
LY2951742	Humanized antibody against CGRP	Prophylactic treatment	Subcutaneous	Phase II	110,111
ALD403	Humanized antibody against CGRP	Prophylactic treatment	intravenous	Phase II	112
LBR-101	Humanized antibody against CGRP	Prophylactic treatment	Subcutaneous	Phase II	113
AMG 334	Humanized antibody against CGRP receptor	Prophylactic treatment	Subcutaneous	Phase II	In progress (NCT01952574)

Abbreviation: CGRP, calcitonin gene-related peptide.

Figure 1 Idealized scheme depicting modulation by CGRP or BNP of P2X3 and TRPV1 receptors of trigeminal sensory neurons.

Notes: Extracellular CGRP binds to its receptor complex comprising, in addition to the CGRP-binding site, the accessory proteins RAMP and CRL. Once this receptor is activated, it catalyzes the synthesis of cAMP that, in turn, activates PKA to phosphorylate the intracellular domain of the ATP-sensitive P2X3 receptor with subsequent gain of function and facilitation of trigeminal pain signaling. In addition, CGRP receptor activity stimulates P2X3 gene expression to promote synthesis and trafficking of these receptors. No apparent effect by CGRP on TRPV1 receptors is reported. Extracellular BNP binds to its receptor NPR-A, which catalyzes the synthesis of cGMP that, in turn, stimulates phosphorylation of AKT, thereby activating this kinase. Even though the multiple intracellular targets for AKT are not fully known, it is proposed to downregulate (probably via a complex intracellular cascade) the activity of TRPV1 as well as P2X3 receptors with an ultimately inhibitory role of the receptor activity. K⁺ channels crucial for stabilizing membrane potential and controlling firing of action potentials are also shown. Positive and negative signs indicate activation and inhibition, respectively.
Abbreviations: AC, adenylate cyclase; BNP, brain natriuretic peptide; Ca²⁺, calcium channels; CGRP, calcitonin gene-related peptide; CRL, calcitonin receptor-like receptor; K⁺, potassium channels; NPR-A, natriuretic peptide receptor A; PKA, protein kinase A; PKG, protein kinase G; RAMP, receptor activity-modifying protein; TRPV, transient receptor potential vanilloid.