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Stimulatory and Inhibitory Roles of Brain 2-Arachidonoylglycerol in Bombesin-Induced Central Activation of Adrenomedullary Outflow in Rats

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Stimulatory and Inhibitory Roles of Brain 2-Arachidonoylglycerol in Bombesin-Induced Central Activation of Adrenomedullary Outflow in Rats J Pharmacol Sci 121, 157 – 171 (2013) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Full Paper Stimulatory and Inhibitory Roles of Brain 2-Arachidonoylglycerol in Bombesin-Induced Central Activation of Adrenomedullary Outflow in Rats Takahiro Shimizu1,*, Kenjiro Tanaka1, and Kunihiko Yokotani1 1Department of Pharmacology, School of Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan Received September 9, 2012; Accepted December 19, 2012 Abstract. 2-Arachidonoylglycerol (2-AG) is recognized as a potent endocannabinoid, which reduces synaptic transmission through cannabinoid CB1 receptors, and is hydrolyzed by mono- acylglycerol lipase (MGL) to arachidonic acid (AA), a cyclooxygenase substrate. We already reported that centrally administered MGL and cyclooxygenase inhibitors each reduced the intra- cerebroventricularly (i.c.v.) administered bombesin-induced secretion of adrenal catecholamines, while a centrally administered CB1-antagonist potentiated the response, indirectly suggesting bidirectional roles of brain 2-AG (stimulatory and inhibitory roles) in the bombesin-induced response. In the present study, we separately examined these bidirectional roles using 2-AG and 2-AG ether (2-AG-E) (stable 2-AG analog for MGL) in rats. 2-AG (0.5 μmol/animal, i.c.v.), but not 2-AG-E (0.5 μmol/animal, i.c.v.), elevated basal plasma catecholamines with JZL184 (MGL inhibitor)- and indomethacin (cyclooxygenase inhibitor)-sensitive brain mechanisms. 2-AG-E (0.1 μmol/animal, i.c.v.) effectively reduced the bombesin (1 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines with rimonabant (CB1 antagonist)-sensitive brain mechanisms. Immuno- histochemical studies demonstrated the bombesin-induced activation of diacylglycerol lipase α (2-AG-producing enzyme)-positive spinally projecting neurons in the hypothalamic paraventricular nucleus, a control center of central adrenomedullary outflow. These results directly indicate bidirectional roles of brain 2-AG, a stimulatory role as an AA precursor and an inhibitory role as an endocannabinoid, in the bombesin-induced central adrenomedullary outflow in rats. Keywords: 2-arachidonoylglycerol, monoacylglycerol lipase, cyclooxygenase, cannabinoid CB1 receptor, central adrenomedullary outflow Introduction splanchnic nerves, but intravenous administration of bombesin did not affect the nerve activities in rats (3). Bombesin, a tetradecapeptide originally isolated from We also reported that i.c.v. administered bombesin the skin of the European frog Bombina bombina (1), is a elevated plasma levels of catecholamines (noradrenaline ligand for bombesin BB receptors. This peptide is not and adrenaline) and the elevations were both abolished expressed in mammals, while the mammalian counter- by acute bilateral adrenalectomy in rats (4). Furthermore, parts and the receptors are widely distributed in the we reported that the peptide-induced elevations of plasma mammalian brain (2). Using bombesin, we have been catecholamines were reduced by central pretreatment examining central regulatory mechanisms of sympatho- with ketoprofen (an inhibitor of cyclooxygenase) (5) and adrenomedullary outflow. Previously, we reported that that central pretreatment with indomethacin (another intracerebroventricularly (i.c.v.) administered bombesin inhibitor of cyclooxygenase) reduced the centrally increased nerve activity of the adrenal branch of the administered arachidonic acid (a representative substrate of cyclooxygenase)-induced elevation of plasma cate- *Corresponding author. [email protected] cholamines in rats (6). In addition, we reported that Published online in J-STAGE on February 2, 2013 (in advance) centrally administered prostanoids, produced from doi: 10.1254/jphs.12208FP arachidonic acid by cyclooxygenase-mediated mecha- 157 158 T Shimizu et al nisms, elevated plasma levels of catecholamines in rats uptake-inhibitor of endocannabinoid) potentiated or (7, 8). These results suggest that the cyclooxygenase- reduced the centrally administered bombesin–induced mediated production of active arachidonic acid metabo- elevation of plasma catecholamines, respectively (16). lites (prostanoids) in the brain is involved in the These results suggest that endogenously generated brain bombesin-induced activation of central adrenomedullary endocannabinoid (probably 2-AG) plays bidirectional outflow in rats. roles (a stimulatory role as a precursor of prostanoids Arachidonic acid is found in cellular membrane and an inhibitory role as an endocannabinoid) in the phospholipids in position 2. Phospholipase A2 (PLA2) bombesin-induced elevation of plasma catecholamines hydrolyzes this phospholipid sn-2 ether bond, thereby in rats. directly releasing arachidonic acid (9, 10). However, we In the present study, we attempted to separately reported that central pretreatment with mepacrine (an examine the bidirectional roles of 2-AG by examining inhibitor of PLA2) had no effect on the centrally admin- the effect of centrally administered 2-AG itself on the istered bombesin–induced elevation of plasma catechol- basal plasma catecholamines levels and by examining amines (11), indicating the involvement of a brain the effect of centrally administered 2-AG ether (a stable phospholipase other than PLA2 in the bombesin-induced analog of 2-AG for monoacylglycerol lipase) on the response. A phospholipase C (PLC)-mediated arachidonic centrally administered bombesin–induced elevation of acid producing pathway is also reported: 1) PLC cleaves plasma catecholamines in rats. the phosphodiester bond of membrane phospholipids, resulting in the formation of diacylglycerol (12); 2) Materials and Methods diacylglycerol containing arachidonic acid in position 2 can be hydrolyzed to 2-arachidonoylglycerol (2-AG) by Animals sn-1 selective diacylglycerol lipase (13); and 3) 2-AG All animal experiments were conducted in compliance can be further hydrolyzed by monoacylglycerol lipase to with the guiding principles for the care and use of free arachidonic acid (14, 15). Recently, using inhibitors laboratory animals approved by Kochi University, which of each lipase described above, we indirectly indicated are in accordance with the “Guidelines for Proper the involvement of brain arachidonic acid generated Conduct of Animal Experiments” from the Science by the brain PLC-, diacylglycerol lipase-, and mono- Council of Japan. Male Wistar rats weighing about 350 acylglycerol lipase–mediated pathway in the bombesin- g were used (Japan SLC, Inc., Hamamatsu). Two rats induced responses in rats (11, 16). Actually, this PLC- were kept in one cage, and they were maintained in an mediated pathway has been reported to be a source of air-conditioned room at 22°C – 24°C under a constant arachidonic acid from 2-AG in many cells such as bovine day–night rhythm (14/10 h light–dark cycle, lights on at coronary endothelial cells (17), rabbit aorta (18), and 05:00) for more than 2 weeks and given food (laboratory murine melanoma cells (19). These findings suggest that chow, CE-2; Clea Japan, Hamamatsu) and water ad brain 2-AG generated by the PLC- and diacylglycerol libitum. lipase–mediated pathway functions as a source of brain arachidonic acid during the bombesin-induced elevation Experimental procedures for intracerebroventricular of plasma catecholamines in rats. administration Interestingly, this arachidonic acid source 2-AG has In the morning (09:00 – 10:00), the femoral vein was recently been recognized as a major brain endocannabi- cannulated for infusion of saline (1.2 ml/h) and the noid for cannabinoid CB receptors (20, 21). In the ner- femoral artery was cannulated for collecting blood vous system, 2-AG produced on demand from membrane samples, under urethane anesthesia (1.2 g/kg, i.p.). After phospholipids of postsynaptic neurons acts on pre- these procedures, the rat was placed in a stereotaxic synaptic cannabinoid CB1 receptors, thereby inhibiting apparatus for the brain until the end of each experiment, the release of neurotransmitters (21, 22). The 2-AG as shown in our previous papers (30, 31). The skull was released into the synaptic cleft seems to be rapidly drilled for intracerebroventricular administration of test inactivated by uptake into neurons (23). This 2-AG– reagents using a stainless-steel cannula (0.3 mm in outer induced retrograde signaling process seems to be involved diameter). The stereotaxic coordinates of the tip of the in widespread effects, including synaptic plasticity (24), cannula were as follows (in mm): AP −0.8, L 1.5, V 4.0 analgesia (25), neuroprotection and neurotoxicity (26, (AP, anterior from the bregma; L, lateral from the 27), food intake (24, 28), and also in the baroreflex- midline; V, below the surface of the brain), according to evoked central sympathetic modulation (29). Recently, the rat brain atlas (32). Three hours were allowed to we reported that central pretreatment with AM 251 (an elapse before the application of reagents. antagonist of cannabinoid CB1 receptors) or AM 404 (an Brain 2-AG in Adrenomedullary Outflow 159 Drug administration detector, +450 mV potential against an Ag/AgCl refer- 2-AG or 2-AG ether dissolved in 100% N,N-dimethyl- ence electrode; column, Eicompack CA-50DS, 2.1 formamide (DMF) was slowly administered into the mm × 150 mm (Eicom); mobile phase, 0.1 M NaH2PO4− right lateral ventricle in a volume of 2.5 μl/animal using Na2HPO4 buffer (pH 6.0) containing 50 mg/l disodium the cannula connected to a 10-μl Hamilton syringe, and EDTA, 0.75 g/l sodium 1-octanesulfonate,
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