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.

Characterisation of the vasorelaxant properties of the novel endocannabinoid N‐arachidonoyl‐dopamine (NADA)

“…To assess the involvement of VRs, capsazepine (10 mM, a VR antagonist) was added to the buffer 20 min before preconstriction (Zygmunt et al, 1999). Also, some vessels were incubated for 1 h with the vanilloid agonist capsaicin (10 mM) to deplete the sensory nerves of neurotransmitters.…”

“…Also, some vessels were incubated for 1 h with the vanilloid agonist capsaicin (10 mM) to deplete the sensory nerves of neurotransmitters. This was followed by a 20-min washout period (Zygmunt et al, 1999;Harris et al, 2002).…”

“…One of the most interesting proposals has been that anandamide stimulates VRs on perivascular sensory nerves, and acts via the release of the vasodilator neurotransmitter calcitonin gene-related peptide (CGRP; Zygmunt et al, 1999;Ralevic et al, 2000). Whether this action can account for the entire endocannabinoid vasorelaxant response has yet to be clarified, as further studies have not found that the entire response to anandamide is mediated via sensory nerves (Ralevic et al, 2000;Harris et al, 2002).…”

A solid-phase method for the extraction and measurement of anandamide from multiple human biomatrices

“…Through receptor activation, AEA exhibits pleiotropic physiological effects including hypothermia, anti-nociception, vasodilation and anti-inflammatory responses [2,6] and has been implicated in several physiological functions and conditions ranging from analgesia, reproduction, vascular tone, obesity, cancer, schizophrenia and multiple sclerosis [7].…”

Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells

“…The cellular effects of AEA, apart from CB receptor activity, have been associated with agonist activity at the transient receptor potential vanilloid 1 (TRPV1) (Zygmunt et al 1999) and metabolites from a range of intracellular enzymes known to be involved in the endocannabinoid biotransformation, such as fatty acid hydrolase (FAAH), cyclooxygenase (COX) and lipooxygenase (LOX), may also contribute to the cytotoxicity of AEA. Furthermore, AEA has been found dose-dependently to induce transcriptional activation of peroxisome proliferator-activated receptor (PPAR) γ, but also directly to bind to PPARγ and act as an agonist (Bouaboula et al 2005).…”