Cited by 2,142Cannabis and Cannabinoid ResearchIon Channels and ReceptorsPain Mechanisms and Treatments

Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

Zygmunt, Peter M., Petersson, Jesper, Andersson, David A., Chuang, Huai-hu, Sørgård, Morten, Di Marzo, Vincenzo, Julius, David, Högestätt, Edward D.·1999·Nature

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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Crossref · 10.1038/22761

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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).”
  • Microglia are a core source of endocannabinoids.

    “Microglia are a core source of endocannabinoids”
  • 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].”

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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
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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