Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
Abstract
The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
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AEA and 2-AG are produced via NAPE-PLD- and DAGL-dependent pathways, respectively, and can bind to CB1 and CB2.
“endogenous cannabinoids can produce endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are produced via N-acyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD)– and diacylglycerol lipase (DAGL)–dependent pathways, respectively. AEA and 2-AG can bind to cannabinoid receptors CB1 and CB2 (154).”
From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [154]
Microglia are a core source of endocannabinoids.
“Microglia are a core source of endocannabinoids”
From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [154]
AEA actions are not restricted to CB1R; ECBs also act at CB2R, GPR55, TRPV1, and other G protein subtypes such as Gs and/or Gq11.
“Enriching the picture further, the actions of AEA are not restricted to CB1R, given that ECBs also act, sometimes in a non-retrograde manner, at CB2R [30], GPR55 [31], and TRPV1 (transient receptor potential vanilloid type 1) channels [32–34], as well as other G protein subtypes such as Gs and/or Gq11 [35,36].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [32]
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- Authors
- Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H.-H., Sørgård, M., Di Marzo, V., Julius, D., & Högestätt, E. D.
- Affiliations
- Lund University (SE)
- University of California, San Francisco (US)
- Corresponding author
- Högestätt, Edward D.
- Venue
- Nature
- Published
- 1999-07
- Volume
- 400
- Issue
- 6743
- Pages
- 452-457
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1488329806
- Cited by
- 2,142
- References
- 30
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 38 · 2023: 46 · 2022: 45 · 2021: 62 · 2020: 57 · 2019: 47 · 2018: 51 · 2017: 77 · 2016: 67 · 2015: 72 · 2014: 84 · 2013: 102 · 2012: 105
- FWCI
- 53.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- anandamide, vanilloid receptor, TRPV1, vasodilation, calcitonin gene-related peptide, sensory nerves, capsaicin, capsazepine, cannabinoid receptors, CB1 receptor, CB2 receptor, 2-arachidonoylglycerol, endocannabinoid system, vascular smooth muscle
- MeSH terms
- Calcitonin Gene-Related Peptide Receptor Antagonists, Animals, Arachidonic Acids, Basilar Artery, Capsaicin, Cell Line, Female, Guinea Pigs, Hepatic Artery, Neurons, Afferent, Peptide Fragments, Receptors, Drug, Recombinant Proteins, Vasodilator Agents, Xenopus, Calcium Channels, Calcitonin Gene-Related Peptide, Rats, Wistar, Receptors, Cannabinoid, Receptor, Cannabinoid, CB2, Rats, Polyunsaturated Alkamides, Endocannabinoids, In Vitro Techniques
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