Abstract
Migraine is a common and debilitating neurovascular disorder which affects approximately 15% of the population and presents a significant burden on those living with the disease. During a migraine attack, increased levels of the vasoactive neuropeptide calcitonin gene-related peptide (CGRP) are observed. However, the exact mechanisms of migraine remain unknown. The CGRP-responsive amylin 1 (AMY1) receptor, comprised of the calcitonin receptor (CTR) and receptor activity-modifying protein 1 (RAMP1), has recently been implicated as potentially relevant in migraine signalling. While expression data is available for CGRP and these receptor subunits separately, the expression of these proteins have never been explored in conjunction. Investigating the distribution of this expression in migraine-relevant regions which are documented to express CGRP-binding sites may contribute to elucidating migraine mechanisms. Thus, the present study aimed to investigate the spatial distribution of CTR relative to CGRP within migraine-relevant regions, including the lateral medulla, dorsolateral pons, and the amygdala. In three female and three male mice, immunohistochemistry was performed for the detection of CGRP-like and CTR-like immunoreactivity within these regions, with cell markers included to indicate potential immunoreactivity within cell bodies. Findings were visualised using confocal microscopy. Bright and dense CGRP-like immunoreactivity was predominantly observed in pearl-like fibres, particularly within the spinal trigeminal nucleus of the lateral medulla, the external division of the lateral parabrachial nucleus, and the capsular region of the central amygdala. Strong CTR-like immunoreactivity was observed in a combination of fibres and cell bodies, with regions of expression including the area postrema of the lateral medulla, throughout the parabrachial nucleus and locus coeruleus, and in the lateral region of the central amygdala. No visual qualitative difference was apparent in CGRP-like or CTR-like immunoreactivity between male and female mice. Throughout all sections, no co-localisation of CGRP-like and CTR-like immunoreactivity was observed; however, CGRP-like and CTR-like immunoreactivity was consistently found in close proximity to each other.
These findings suggest that in some migraine-relevant brain regions, CGRP may activate CTR (potentially with RAMP1) in a paracrine manner, and therefore supports a potential role of the AMY1 receptor in migraine.