Mechanisms Underlying Tissue Selectivity of Anandamide and Other Vanilloid Receptor Agonists

Abstract

Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.

Potentiation of Anandamide Effects in Mesenteric Beds Isolated from Endotoxemic Rats

“…Although a single population of vanilloid receptors has been reported in mesenteric beds from guinea pig (Andersson et al, 2002), the finding that capsazepine, at the concentration used in our study, had antagonized the effects of anandamide, but not those of capsaicin, is in accordance with the proposal of different vanilloid receptor subtypes (Szallasi and Blumberg, 1996) with different susceptibilities to blockade by capsazepine (Griffiths et al, 1996;Liu et al, 1998).…”

Novel Compounds That Interact with Both Leukotriene B4 Receptors and Vanilloid TRPV1 Receptors

“…Thus, the low TRPV1 receptor efficacy of LTB 4 ethanolamide would explain the lack of a TRPV1-mediated contraction in this tissue compared with the high expressing recombinant CHO cell line and DRG neurons. It is known that anandamide acts as a full TRPV1 receptor agonist in isolated blood vessels, but it acts as a low-efficacy agonist in guinea pig bronchus and trigeminal neurons where it antagonizes the action of capsaicin (Andersson et al, 2002;Roberts et al, 2002;Ross, 2003).…”

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1and CB2

“…Although anandamide may be less potent as a TRPV1 agonist than as a CB 1 receptor agonist, elevation of its endogenous levels with fatty acid amide hydrolase (FAAH) inhibitors [e.g., cyclohexylcarbamic acid 3Ј-carbamoyl-biphenyl-3-yl ester (URB597)] can lead to effects that are mediated by TRPV1 (Maione et al, 2006;Morgese et al, 2007;Rubino et al, 2008). This, together with data indicating that exogenous anandamide can exert effects at TRPV1 in a way sensitive to inhibitors of anandamide cellular uptake in HEK293 cells ), trigeminal neurons (Price et al, 2005b), and, ex vivo, in mesenteric arteries (Andersson et al, 2002) represents strong indirect evidence that both endogenous and exogenous anandamide reaches its intracellular binding site on this molecular target.…”