Background and purpose: The endocannabinoid N-arachidonoylethanolamide (anandamide) is co-synthesized with other N-acylethanolamides, namely N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which have been shown to potentiate anandamide responses (so-called 'entourage effects') in non-vascular tissues. It remains unclear whether such interactions occur in the circulation. Experimental approach: In rat isolated small mesenteric arteries, the effects of PEA and OEA on relaxation to anandamide and tissue contents of the N-acylethanolamides were examined under myographic conditions. Key results: Anandamide-induced relaxation was potentiated by pretreatment with PEA (10 mM) or OEA (1 mM), or in combination. The potentiation by PEA and OEA was endothelium-independent and abolished by treatment with capsaicin (10 mM), which desensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor system, or by the TRPV1 receptor antagonist, N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) (2 mM). It was also observed at molar ratios of anandamide and PEA (or OEA) similar to those found in mesenteric arteries. PEA and inhibition of anandamide hydrolysis by 3 0 -carbamoylbiphenyl-3-yl-cyclohexylcarbamate (URB597) (1 mM) additively potentiated anandamide responses. On the other hand, PEA and OEA also induced vasorelaxation per se (rank order of potency: anandamide4OEA4PEA), but relaxation to the three N-acylethanolamides displayed different sensitivity to treatment with capsaicin, SB366791 and URB597. For example, relaxations to anandamide and OEA, but not PEA, were attenuated by both capsaicin and SB366791. Conclusion and implications: This study shows that PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxation per se, suggesting a function for the N-acylethanolamides in vascular control.

Preclinical research has suggested that the endocannabinoid system may be involved in the etiology and/or treatment of depression; however, there are no detailed studies examining endocannabinoid content in patients with clinical depression. This study examined the endocannabinoids (anandamide; AEA) and 2-arachidonylglycerol (2-AG) in serum from ambulatory, medication-free female patients diagnosed with minor or major depression, and in controls matched for demographic characteristics. Serum 2-AG content was significantly decreased in patients diagnosed with major depression, and this decrease was correlated significantly and negatively with duration of the depressive episode, such that 2-AG content was progressively lower the longer the depressive episode. While AEA was not associated with major depression per se, a strong negative correlation was found between serum AEA content and Hamilton ratings for cognitive and somatic anxiety, suggesting that AEA content may relate to the anxiety dimension of affective disorders. In subjects with minor depression, serum AEA was significantly elevated, with 2-AG content demonstrating a similar, but statistically insignificant trend. These are the first clinical data to indicate that the endocannabinoid system may be disturbed in affective disease, and suggest that future research is required to determine the relevance of these changes with respect to disease manifestation and pharmacotherapy.

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1 The cannabinoid arachidonyl ethanolamide (anandamide) caused concentration-dependent relaxation of 5-HT-precontracted, myograph-mounted, segments of rat left anterior descending coronary artery. 2 This relaxation was endothelium-independent, una ected by the fatty acid amide hydrolase inhibitor, arachidonyl tri¯uoromethyl ketone (10 mM), and mimicked by the non-hydrolysable anandamide derivative, methanandamide. 3 Relaxations to anandamide were attenuated by the cannabinoid receptor antagonist, SR 141716A (3 mM), but una ected by AM 251 (1 mM) and AM 630 (1 mM), more selective antagonists of cannabinoid CB 1 and CB 2 receptors respectively. Palmitoylethanolamide, a selective CB 2 receptor agonist, did not relax precontracted coronary arteries. 4 Anandamide relaxations were not a ected by inhibition of sensory nerve transmission with capsaicin (10 mM) or blockade of vanilloid VR1 receptors with capsazepine (5 mM). Nevertheless capsaicin relaxed coronary arteries in a concentration-dependent and capsazepine-sensitive manner, con®rming functional sensory nerves were present. In contrast, capsazepine and capsaicin did inhibit anandamide relaxations in methoxamine-precontracted rat small mesenteric arteries. 5 Relaxations to anandamide were inhibited by TEA (1 mM) or iberiotoxin (50 nM), blockers of large conductance, Ca 2+ -activated K + channels (BK Ca ). Gap junction inhibition with 18a-glycyrrhetinic acid (100 mM) did not a ect anandamide relaxations. 6 This study shows anandamide relaxes the rat coronary artery by a novel mechanism. Anandamide-induced relaxations do not involve the endothelium, degradation into active metabolites, or activation of cannabinoid CB 1 or CB 2 receptors, but may involve activation of BK Ca . Vanilloid receptor activation also has no role in the e ects of anandamide in coronary arteries, even though functional sensory nerves are present. British Journal of Pharmacology (2001) 134, 921 ± 929