Abstract
BackgroundBased on the current understanding of the role of neuropeptide signalling in migraine, we explored the therapeutic potential of a specific cannabinoid agonist. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2′-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate Gi/o-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition.MethodsThe experiments were performed using the hemi-skull model and dissected TGs from male Sprague-Dawley rats. CGRP release was induced by either 60 mM K+ (for depolarization-induced stimulation) or 100 nM capsaicin (for transient receptor potential vanilloid 1 (TRPV1) -induced stimulation) and measured using an enzyme-linked immunosorbent assay. The analysis of CGRP release data was combined with immunohistochemistry in order to study the cellular localization of CB1, cannabinoid receptor type 2 (CB2), CGRP and receptor activity modifying protein 1 (RAMP1), a subunit of the functional CGRP receptor, in the TG.ResultsCB1 was predominantly expressed in neuronal somas in which colocalization with CGRP was observed. Furthermore, CB1 exhibited colocalization with RAMP1 in neuronal Aδ-fibres but was not clearly expressed in the CGRP-immunoreactive C-fibres. CB2 was mainly expressed in satellite glial cells and did not show substantial colocalization with either CGRP or RAMP1. Without stimulation, 140 nM ACEA per se caused a significant increase in CGRP release in the dura but not TG, compared to vehicle. Furthermore, 140 nM ACEA did not significantly modify neither K+- nor capsaicin-induced CGRP release. However, when the TRPV1 blocker AMG9810 (1 mM) was coapplied with ACEA, K+-induced CGRP release was significantly attenuated in the TG and dura.ConclusionsResults from the present study indicate that ACEA per se does not exhibit antimigraine potential due to its dual agonistic properties, resulting in activation of both CB1 and TRPV1, and thereby inhibition and stimulation of CGRP release, respectively.
Highlights
Migraine is a highly debilitating neurological condition linked to the sensory innervation of cranial blood vessels by the trigeminal nerves, together known as the trigeminovascular system (TVS)
Using the rat hemi-skull model, this study aims to determine the effect of arachidonyl-2′-chloroethylamide (ACEA), a synthetic anandamide analogue with high potency and selectivity for cannabinoid receptors type 1 (CB1) [34], on K +- and capsaicin-induced calcitonin gene-related peptide (CGRP) release from the dura and trigeminal ganglion (TG) of male Sprague-Dawley rats
Since ACEA is a potent and highly selective CB1 agonist [34], we sought to examine the therapeutic potential of ACEA in migraine pathology by investigating whether ACEA per se, affects CGRP levels in the dura and TG of male Sprague-Dawley rats
Summary
Migraine is a highly debilitating neurological condition linked to the sensory innervation of cranial blood vessels by the trigeminal nerves, together known as the trigeminovascular system (TVS). Christiansen et al The Journal of Headache and Pain (2022) 23:30 peptide (CGRP), a vasodilator found in trigeminal neurons, increase significantly in craniovascular regions during the headache phase of migraine attacks, suggesting a crucial role for CGRP in migraine pathology [1]. According to the current view on migraine pathophysiology, hypothalamic activation during the premonitory phase of a migraine attack results in activation of the TNC, which in turn leads to activation of the TG. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2′-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate G i/o-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition
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