Possible inhibitory roles of endogenous 2-arachidonoylglycerol during corticotropin-releasing factor-induced activation of central sympatho-adrenomedullary outflow in anesthetized rats.
We previously reported that intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (CRF) (0.5-3.0 nmol/animal) dose-dependently elevates plasma noradrenaline and adrenaline through brain phospholipase C-, diacylglycerol lipase- and prostanoids-mediated mechanisms in rats. Diacylglycerol produced by phospholipase C from phospholipids can be hydrolyzed by diacylglycerol lipase into 2-arachidonoylglycerol, which may be further hydrolyzed by monoacylglycerol lipase into arachidonic acid, a precursor of prostanoids. Recently, 2-arachidonoylglycerol has been recognized as a major brain endocannabinoid, which can modulate synaptic transmission through presynaptic cannabinoid CB(1) receptors. Released 2-arachidonoylglycerol is rapidly deactivated by uptake into cells and enzymatic hydrolysis. In the present study, therefore, we examined (1) the involvement of brain 2-arachidonoylglycerol, (2) the regulatory role of 2-arachidonoylglycerol as a brain endocannabinoid, and (3) the effect of exogenous cannabinoid receptor agonist, on the CRF-induced elevation of plasma noradrenaline and adrenaline using anesthetized rats. The elevation of both catecholamines induced by a submaximal dose of CRF (1.5 nmol/animal, i.c.v.) was reduced by i.c.v. administered MAFP (monoacylglycerol lipase inhibitor) (0.7 and 1.4 micromol/animal), AM 404 (endocannabinoid uptake-inhibitor) (80 and 250 nmol/animal) and ACEA (cannabinoid CB(1) receptor agonist) (0.7 and 1.4 micromol/animal), while AM 251 (cannabinoid CB(1) receptor antagonist) (90 and 180 nmol/animal, i.c.v.) potentiated the response induced by a small dose of CRF (0.5 nmol/animal, i.c.v.). These results suggest a possibility that 2-arachidonoylglycerol is endogenously generated in the brain during CRF-induced activation of central sympatho-adrenomedullary outflow, thereby inhibiting the peptide-induced response by activation of brain cannabinoid CB(1) receptors in anesthetized rats.
Department of Pharmacology, School of Medicine, Kochi University, Nankoku, Kochi, Japan. shimizu@kochi-u.ac.jp
Takahiro
T
Shimizu
Lianyi
L
Lu
Kunihiko
K
Yokotani
D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism*; D000758:Anesthesia; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002395:Catecholamines / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism*
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators; D002395:Catecholamines; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; C119325:arachidonyl-2-chloroethylamide; C103505:AM 251; C094503:glyceryl 2-arachidonate; D003346:Corticotropin-Releasing Hormone; D008994:Monoacylglycerol Lipases; C107594:N-(4-hydroxyphenyl)arachidonylamide