The Endogenous Cannabinoid, Anandamide, Activates the Hypothalamo-Pituitary-Adrenal Axis in CB₁ Cannabinoid Receptor Knockout Mice

Abstract

The purpose of this study was to investigate the effects of the endogenous cannabinoid arachidonoyl-ethanolamide, anandamide (AEA), on the activity of the hypothalamo-pituitary-adrenal (HPA) axis in cannabinoid receptor (CB₁ receptor) inactivated (KO) mice. A low dose (0.01 mg/kg i.p.) of AEA significantly increased plasma corticotropin (ACTH) and corticosterone concentrations in both wild-type (+/+) and in mutant (–/–) animals. In each case, hormone levels reached their peaks at 90 min after AEA administration. In a parallel experiment, AEA administration was preceded by the injection of SR 141716A (1.0 mg/kg), a selective and potent CB₁ receptor antagonist, or of capsazepine (5.0 mg/kg), a potent vanilloid receptor of type 1 (VR1) antagonist. The latter drugs did not prevent the effects of AEA on the HPA axis. Using Fos protein immunohistochemistry, we observed that the parvocellular part of the hypothalamic paraventricular nucleus (PVN) was activated as early as 45 min after AEA injection and reached peak levels after 60 min in both +/+ and –/– mice. Furthermore, the CB₁ and VR1 receptor antagonists did not block the effects of AEA on Fos immunoreactivity. The results strongly support the view that activation of the HPA axis produced by AEA possibly occurs via a currently unknown (CB_x) cannabinoid receptor present in PVN.

Cannabinoids and Their Interactions with Diazepam on Modulation of Serum Corticosterone Concentration in Male Mice

“…Our results showed that the AM404 or URB597-induced elevation in CORT was blocked when these compounds were co-administered with cannabinoid CB1 receptor antagonist/inverse agonist AM251. These results are consistent with previous study which showed that the anandamide-induced elevation in corticosterone level was blocked by the injection of a selective and potent CB1 receptor antagonist SR141716A Rimonabant [29]. Considering these data, it could be suggest that the opposite effect of endogenous and exogenous cannabinoid receptor agonists on CORT level might be due to the involvement of other receptor/pathway systems in modulation of HPA axis.…”

“…Considering these data, it could be suggest that the opposite effect of endogenous and exogenous cannabinoid receptor agonists on CORT level might be due to the involvement of other receptor/pathway systems in modulation of HPA axis. Further evidence supporting the existence of another receptor/pathway system for modulation of corticosterone release by endocannabinoid system came from a study by Wenger et al [29] in which administration of the endogenous cannabinoid anandamide was shown to increase plasma corticosterone concentrations in CB1 receptor knockout mice.…”

Characterization of two duplicate zebrafish Cb2-like cannabinoid receptors

“…Zebrafish Cb2 receptors have been observed in the rostral part of the pituitary gland, specifically, in the rostral pars distalis and proximal pars distalis. This finding is important, since it has been described that both exogenous and endogenous cannabinoids can influence hormone secretion at pituitary and hypothalamic levels (De Miguel et al, 1998;Wenger et al, 2003).…”

Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: A non-genomic anti-inflammatory switch

“…Peripheral treatment of cannabinoid CB 1 receptor knockout mice with AEA unexpectedly resulted in a significant elevation of plasma ACTH and corticosterone, and an increase in the hypothalamic paraventricular nucleus Fos immunoreactivity (Wenger et al, 2003). This effect was not blocked by antagonism of either cannabinoid CB 1 receptor or the transient receptor potential vanilloid type 1 (TRPV1) receptor, and suggested the involvement of a non-CB 1 type of cannabinoid receptor.…”