title: Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat.
abstract: We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (1, 5 or 10 nmol/animal), a nicotinic acetylcholine receptor agonist, dose-dependently induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla by brain diacylglycerol lipase- (DGL), monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms. Diacylglycerol is hydrolyzed by DGL into 2-arachidonoylglycerol (2-AG), which is further hydrolyzed by MGL to arachidonic acid (AA), a cyclooxygenase substrate. These findings suggest that brain 2-AG-derived AA is involved in the (±)-epibatidine-induced response. This AA precursor 2-AG is also a major brain endocannabinoid, which inhibits synaptic transmission through presynaptic cannabinoid CB1 receptors. Released 2-AG into the synaptic cleft is rapidly inactivated by cellular uptake. Here, we examined a role of brain 2-AG as an endocannabinoid in the (±)-epibatidine-induced activation of central adrenomedullary outflow using anesthetized male Wistar rats. In central presence of AM251 (CB1 antagonist) (90 and 180 nmol/animal, i.c.v.), (±)-epibatidine elevated plasma catecholamines even at an ineffective dose (1 nmol/animal, i.c.v.). Central pretreatment with ACEA (CB1 agonist) (0.7 and 1.4 μmol/animal, i.c.v.), 2-AG ether (stable 2-AG analog for MGL) (0.5 and 1.0 μmol/animal, i.c.v.) or AM404 (endocannabinoid uptake inhibitor) (80 and 250 nmol/animal, i.c.v.) significantly reduced an effective dose of (±)-epibatidine- (5 nmol/animal, i.c.v.) induced elevation of plasma catecholamines, and AM251 (90 and 180 nmol/animal, i.c.v.) centrally abolished the reduction induced by 2-AG ether (1.0 μmol/animal, i.c.v.) or AM404 (250 nmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activated DGLα-positive spinally projecting neurons in the hypothalamic paraventricular nucleus, a control center of central adrenomedullary system. These results suggest a possibility that a brain endocannabinoid, probably 2-AG, plays an inhibitory role in (±)-epibatidine-induced activation of central adrenomedullary outflow through brain CB1 receptors in the rat.
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan. Electronic address: shimizu@kochi-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Neurobiology and Anatomy, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Youichirou
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Neurosurgery, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Yawata
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Taniuchi
authors.affiliation: Department of Neurosurgery, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueba
authors.affiliation: Department of Neurobiology and Anatomy, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yuri
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Saito
mesh_terms: D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000008:administration & dosage / Q000378:metabolism*; D005989:Glycerides / Q000008:administration & dosage / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002395:Catecholamines; D063388:Endocannabinoids; D005989:Glycerides; D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; C103505:AM 251; C094503:glyceryl 2-arachidonate; C082748:epibatidine; C107594:N-(4-hydroxyphenyl)arachidonylamide
keywords: (±)-Epibatidine; 2-Arachidonoylglycerol; Brain; Cannabinoid CB(1) receptor; Central adrenomedullary outflow; Endocannabinoid