Beyond CGRP: The calcitonin peptide family as targets for migraine and pain

Abstract

The CGRP system has emerged as a key pharmacological target for the treatment of migraine. However, some individuals who suffer from migraine have low or no response to anti-CGRP or other treatments, suggesting the need for additional clinical targets. CGRP belongs to the calcitonin family of peptides, which includes calcitonin, amylin, adrenomedullin and adrenomedullin 2. These peptides display a range of pro-nociceptive and anti-nociceptive actions, in primary headache conditions such as migraine. Calcitonin family peptides also show expression at sites relevant to migraine and pain. This suggests that calcitonin family peptides and their receptors, beyond CGRP, may be therapeutically useful in the treatment of migraine and other pain disorders. This review considers the localisation of the calcitonin family in peripheral pain pathways and discusses how they may contribute to migraine and pain. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Keywords: CGRP; adrenomedullin; amylin; calcitonin; migraine; pain.

Figure 1:. Amino acid sequences of the human CT peptide family.

In all peptides a disulphide bond is formed between the two N-terminal cysteines and each have a C-terminal amide (not shown). A) The human CT peptide family, omitting the N-terminal extensions of AM and AM2. B) Alignment of full-length AM and AM2. C) Sequence alignment of human α-CGRP and Amy. D) Overlap in amino acids between human and rodent amylin and αCGRP. Alignment performed in Clustal Omega (Sievers et al., 2011) and analysed using BoxShade (http://www.ch.embnet.org/software/BOX_form.html). For A-C, black indicates an exact match, grey indicates 70–100% similarity and white indicates <70% similarity. For D, dark blue indicates that an amino acid is shared across all four peptides; light blue indicates that an amino acid is shared across three peptides. Substantial sequence overlap is observed at the N and C terminus of the peptides (underlined).

Figure 2:. The human CT receptor family subunits, receptors, and pharmacology.

The relative activities of agonists and antagonists at human receptors are shown with arrows to indicate at which receptors they are most active. The relatively high potency of CT reported at the human AMY receptors likely relates to the activation of free CTR, not AMY in these systems. Solid arrows indicate relatively potent activity compared to dashed arrows, which indicate weaker activity (Hay et al., 2018). Created with BioRender.com.

Figure 3:. Cross-reactive anti-amylin and anti-CGRP antibodies can confound results.

A) The relationship between antigen expression and antibody cross-reactivity. Highly cross-reactive antibodies will display immunoreactivity in tissues with low to high antigen expression whereas, antibodies with low cross-reactivity will only display immunoreactivity if the tissue highly expresses the antigen. B) Cross-reactive anti-CGRP antibodies are known to stain the β-cells of pancreatic islets which highly express amylin and anti-CGRP antibodies that do not display cross-reactivity for amylin have been reported not to detect CGRP in pancreatic β-cells. C) Cross-reactive anti-amylin antibodies are known to stain neuronal vesicles which highly express CGRP and anti-amylin antibodies that do not display cross-reactivity for CGRP have been reported not to detect amylin in some neuronal vesicles. Created with BioRender.com.

Figure 4:. Summary of the expression of the CT family of peptides in the TG, DRG, spinal cord and STN of rodent and humans.

Distribution of α-CGRP, β-CGRP, AM, AM2, Pro-CT, CT and amylin mRNA and protein in structures related to migraine and pain. Expression where reports are conflicting or weak/no expression is observed have been omitted. Interpretation of these data is difficult as the mRNA probes and in particular antibodies used have limited characterisation, therefore caution should be applied. In some cases, the expression of a particular peptide has not been investigated, leaving a knowledge deficit. Created with BioRender.com.