Abstract
Endogenous cannabinoids are important signaling molecules in neuroendocrine control
of homeostatic and reproductive functions including stress response and energy metabolism.
The hypothalamic paraventricular and supraoptic nuclei have been shown to release
endocannabinoids, which act as retrograde messengers to modulate the synaptic release
of glutamate during stress response. This study endeavors to elucidate possible interaction
of the endocannabinoid system with the regulation of adrenocortical function at the
adrenal level. Human adrenocortical NCI-H295R cells and normal human adrenal glands
were used to study the possible effects of anandamide and cannabinoid receptor 1 (CB1)
antagonist SR141716A on aldosterone and cortisol secretion. Our data indicate the
expression of CB1 in human adrenal cortex and adrenocortical NCI-H295R cells; CB2
was not expressed. Furthermore, anandamide inhibited basal release and stimulated
release of adrenocortical steroids (corticosterone and aldosterone); this effect was
reversed by CB1 antagonist (SR141716A). Therefore, the endocannabinoid system at the
level of the adrenal, can directly influence adrenocortical steroidogenesis.
Key words
anandamide - CB1 antagonist - cortisol - aldosterone
References
1
Tsigos C, Chrousos GP.
Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.
J Psychosom Res.
2002;
53
865-871
2
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE.
Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical
responsiveness.
Front Neuroendocrinol.
2003;
24
151-180
3
Bornstein SR, Engeland WC, Ehrhart-Bornstein M, Herman JP.
Dissociation of ACTH and glucocorticoids.
Trends Endocrinol Metab.
2008;
19
175-180
4
Stowasser M, Gunasekera TG, Gordon RD.
Familial varieties of primary aldosteronism.
Clin Exp Pharmacol Physiol.
2001;
28
1087-1090
5
Mechoulam R, Fride E, Di M V.
Endocannabinoids.
Eur J Pharmacol.
1998;
359
1-18
6
Fernandez-Lopez D, Pazos MR, Tolon RM, Moro MA, Romero J, Lizasoain I, Martínez-Orgado J.
The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic
encephalopathy in newborn rats.
Pediatr Res.
2007;
62
255-260
7
Galiegue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D,
Le Fur G, Casellas P.
Expression of central and peripheral cannabinoid receptors in human immune tissues
and leukocyte subpopulations.
Eur J Biochem.
1995;
232
54-61
8
Pacher P, Ungvari Z.
Pleiotropic effects of the CB2 cannabinoid receptor activation on human monocyte migration:
implications for atherosclerosis and inflammatory diseases.
Am J Physiol Heart Circ Physiol.
2008;
294
H1133-H1134
9
Diaz-Asensio C, Setien R, Echevarria E, Casis L, Casis E, Garrido A, Casis O.
Type 1 diabetes alters brain cannabinoid receptor expression and phosphorylation status
in rats.
Horm Metab Res.
2008;
40
454-458
10
Piomelli D.
The molecular logic of endocannabinoid signalling.
Nat Rev Neurosci.
2003;
4
873-884
11
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R.
The emerging role of the endocannabinoid system in endocrine regulation and energy
balance.
Endocr Rev.
2006;
27
73-100
12
Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J, Pasquali R,
Lutz B, Stalla GK, Pagotto U.
Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal
axis function.
Endocrinology.
2007;
148
1574-1581
13
Barna I, Zelena D, Arszovszki AC, Ledent C.
The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation:
in vivo and in vitro studies in CB1 receptor knockout mice.
Life Sci.
2004;
75
2959-2970
14
Haller J, Varga B, Ledent C, Barna I, Freund TF.
Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social
behaviour in mice.
Eur J Neurosci.
2004;
19
1906-1912
15
Scheen AJ, Paquot N.
Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders.
Best Pract Res Clin Endocrinol Metab.
2009;
23
103-116
16
Kanczkowski W, Morawietz H, Ziegler CG, Funk RH, Schmitz G, Zacharowski K, Mohn CE,
Ehrhart-Bornstein M, Bornstein SR.
Pam3CSK4 and LTA-TLRs ligands associated with microdomains induce IL8 production in
human adrenocortical cancer cells.
Horm Metab Res.
2007;
39
457-460
17
Fernandez-Solari J, Scorticati C, Mohn C, De Laurentiis A, Billi S, Franchi A, McCann SM,
Rettori V.
Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid
system.
Proc Natl Acad Sci USA.
2004;
101
3264-3268
18
Scorticati C, Fernandez-Solari J, De Laurentiis A, Mohn C, Prestifilippo JP, Lasaga M,
Seilicovich A, Billi S, Franchi A, McCann SM, Rettori V.
The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion
is reversed by estrogen.
Proc Natl Acad Sci USA.
2004;
101
11891-11896
19
Weidenfeld J, Feldman S, Mechoulam R.
Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the
hypothalamo-pituitary-adrenal axis in the rat.
Neuroendocrinology.
1994;
59
110-112
20
Wenger T, Jamali KA, Juaneda C, Leonardelli J, Tramu G.
Arachidonyl ethanolamide (anandamide) activates the parvocellular part of hypothalamic
paraventricular nucleus.
Biochem Biophys Res Commun.
1997;
237
724-728
21
Wade MR, Degroot A, Nomikos GG.
Cannabinoid CB1 receptor antagonism modulates plasma corticosterone in rodents.
Eur J Pharmacol.
2006;
551
162-167
22
Navarro M, Hernandez E, Munoz RM, del Arco I, Villanúa MA, Carrera MR, Rodríguez de
Fonseca F.
Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces
anxiety-like responses in the rat.
Neuroreport.
1997;
8
491-496
23
Gorzalka BB, Hill MN, Hillard CJ.
Regulation of endocannabinoid signaling by stress: implications for stress-related
affective disorders.
Neurosci Biobehav Rev.
2008;
32
1152-1160
24
Manzanares J, Corchero J, Fuentes JA.
Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin
hormone and corticosterone plasma concentrations induced by central administration
of delta(9)-tetrahydrocannabinol in rats.
Brain Res.
1999;
839
173-179
25
Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ.
Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal
axis.
Endocrinology.
2004;
145
5431-5438
26
Bird IM, Hanley NA, Word RA, Mathis JM, McCarthy JL, Mason JI, Rainey WE.
Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive
aldosterone secretion.
Endocrinology.
1993;
133
1555-1561
Correspondence
Dr. M. Ehrhart-Bornstein
Carl Gustav Carus Technical University of Dresden Medical Clinic III
Fetscherstraße 74
01307 Dresden
Phone: +49/351/458 61 30
Fax: +49/351/458 63 36
Email: Monika.Bornstein@uniklinikum-dresden.de