Microinjection of a cannabinoid receptor antagonist into the NTS increases baroreflex duration in dogs

Baroreceptor afferent fibers synapse in the nucleus tractus solitarius (NTS) of the medulla. Neuronal cannabinoid (CB)(1) receptors are expressed in the NTS and central administration of CB(1) receptor agonists affect blood pressure (BP) and heart rate. In addition, there is evidence that endocannabinoids are produced in the brain stem. This study examined whether changes in CB(1) receptor activity in the NTS modulated the baroreceptor reflex, contributing to changes seen in BP and heart rate. Baroreflexes were evoked in anesthetized dogs by pressure ramp stimulations of the isolated carotid sinus before and after microinjection of CB(1) receptor agonist WIN-55212-2 (1.25-1.50 pmol) or antagonist SR-141716 (2.5-3.0 pmol) into cardiovascular regions of the NTS. Microinjection of the SR-141716 did not affect baseline BP or baroreflex sensitivity. However, SR-141716 significantly prolonged the time needed to return to the baseline level of BP after the pressure ramp. Microinjection of WIN-55212-2 had no effect on the baroreflex. These data suggest that endocannabinoids can modulate the excitability of NTS neurons involved in the baroreceptor reflex, leading to modulation of baroreflex regulation.     

Ghrelin agonists impact on Fos protein expression in brain areas related to food intake regulation in male C57BL/6 mice

Many peripheral substances, including ghrelin, induce neuronal activation in the brain. In the present study, we compared the effect of subcutaneously administered ghrelin and its three stable agonists: Dpr³ghr ([Dpr(N-octanoyl)³] ghrelin) (Dpr - diaminopropionic acid), YA GHRP-6 (H-Tyr-Ala-His-DTrp-Ala-Trp-DPhe-Lys-NH₂), and JMV1843 (H-Aib-DTrp-D-gTrp-CHO) on the Fos expression in food intake-responsive brain areas such as the hypothalamic paraventricular (PVN) and arcuate (ARC) nuclei, the nucleus of the solitary tract (NTS), and area postrema (AP) in male C57BL/6 mice. Immunohistochemical analysis showed that acute subcutaneous dose of each substance (5 mg/kg b.w.), which induced a significant food intake increase, elevated Fos protein expression in all brain areas studied. Likewise ghrelin, each agonist tested induced distinct Fos expression overall the PVN. In the ARC, ghrelin and its agonists specifically activated similarly distributed neurons. Fos occurrence extended from the anterior (aARC) to middle (mARC) ARC region. In the latter part of the ARC, the Fos profiles were localized bilaterally, especially in the ventromedial portions of the nucleus. In the NTS, all substances tested also significantly increased the number of Fos profiles in neurons, which also revealed specific location, i.e., in the NTS dorsomedial subnucleus (dmNTS) and the area subpostrema (AsP). In addition, cells located nearby the NTS, in the AP, also revealed a significant increase in number of Fos-activated cells. These results demonstrate for the first time that ghrelin agonists, regardless of their different chemical nature, have a significant and similar activating impact on specific groups of neurons that can be a part of the circuits involved in the food intake regulation. Therefore there is a real potency for ghrelin agonists to treat cachexia and food intake disorders. Thus, likewise JMV1843, the other ghrelin agonists represent substances that might be involved in trials for clinical purposes.     

WIN-55,212-2 and SR-141716A alter nicotine-induced changes in locomotor activity, but do not alter nicotine-evoked [3H]dopamine release

Nicotine, the main psychoactive ingredient in tobacco, plays a key role in the development of cigarette smoking addiction. The endocannabinoid system has been demonstrated to have an important role in the motivational and reinforcing effects of drugs. The present study used behavioral and neurochemical techniques to study the interaction of cannabinoid receptors and nicotine pharmacology. In a locomotor activity experiment in rats, the CB(1)/CB(2) cannabinoid receptor agonist WIN-55,212-2 (0.28-2.8 mg/kg) attenuated nicotine (0.4 mg/kg)-induced hyperactivity, but did not alter nicotine (1.0 mg/kg)-induced hypoactivity. In contrast, the selective CB(1) cannabinoid receptor antagonist SR-141716A (1.0 mg/kg) diminished nicotine-induced hypoactivity, but did not alter nicotine-induced hyperactivity. In a neurochemical experiment, rat striatal slices preloaded with [(3)H]dopamine were superfused with WIN-55,212-2 or SR-141716A. A high concentration (100 microM) of WIN-55,212-2 evoked [(3)H]overflow, but this effect was not blocked by the cannabinoid receptor antagonist AM-251. SR-141716A did not evoke [(3)H]overflow, and neither WIN-55,212-2 nor SR-141716A altered nicotine-evoked [(3)H]overflow. Overall, these results indicate a behavioral interaction between cannabinoid receptors and nicotine pharmacology. Likely, WIN-55,212-2 and SR-141716A block nicotine-induced changes in behavior through an indirect mechanism, such as alteration in endocannabinoid regulation of motor circuits, rather than directly through blockade of nicotinic acetylcholine receptors.     

Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors

Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1(-/-), and CB1(-/-)/CB2(-/-) mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.     

侧脑室注射肾上腺髓质素增加大鼠心血管相关核团中c-fos的表达并激活脑内一氧化氮神经元

本研究利用Fos蛋白和一氧化氮合酶(nNOS)双重免疫组化方法,观察侧腑脑室注射肾上腺髓质素(adrenomedullin,ADM)对大鼠心血管相关核中c-fos表达及一氧化氮神经元的影响,以探讨ADM在中枢的作用部位并研究其在中枢的作用是否有NO神经元参与。侧脑室注射ADM(1nmol／kg,3nmol／kg)诱发脑干的孤束核、最后区、蓝斑核、臂旁核和外侧巨细胞旁核,下丘脑的室旁核、视上核才腹内侧核以及前脑的中央杏仁核和外侧缰核等多个部位的心血管中枢出现大量Fos样免疫反应神经元。侧脑室注射ADM(3nmol／kg),引起脑干的孤束核、外侧巨细胞旁核,下丘脑的室旁核、视上核内的Fos-nNOS双标神经元增加;ADM(1nmol／kg)亦可引起室旁核、视上核内的Fos-nNOS双标神经元增加,而对孤束核、外侧巨细胞旁核内的Fos-nNOS双标神经元无影响。降钙素基因相关肽(calcitonin gene—related peptide,CGRP)受体拈抗剂CGRP8-37(30nmol／kg)可明显减弱此效应。以上结果表明,ADM可兴奋脑内多个心血管相关核闭的神经元并激活室旁核、视上核、孤束核及外侧巨细胞核内一氧化氮神经元,此效应可能部分山CGRP受体介导。     

大鼠延髓至下丘脑腹内侧核的儿茶酚胺能投射神经元在胃伤害性刺激后的Fos表达

本实验用ＨＲＰ注入下丘脑腹内侧核结合逆行追踪与抗ＦＯＳ蛋白和抗酪氨酸羟化酶（ＴＨ）抗血清双重免疫细胞化学相结合的三重标记方法,对大鼠孤束核和延髓腹外侧区至下丘脑腹内侧核的儿茶酚胺能投射神经元在胃伤害性刺激后的ｃ－ｆｏｓ表达进行了观察。本文发现孤束核和延髓腹外侧区有七种不同的标记细胞：ＨＲＰ、Ｆｏｓ、ＴＨ单标细胞Ｆｏｓ／ＨＲＰ、Ｆｏｓ／ＴＨ、ＨＲＰ／ＴＨ双标细胞和Ｆｏｓ／ＨＲＰ／ＴＨ三标细胞。上述七种标记细胞主要分布在延髓中段和尾段孤束核的内侧亚核和延髓腹外侧区以及两者之间的网状结构。ＨＲＰ标记细胞以注射侧为主,对侧有少量分布。本文结果证明,大鼠孤束核、延髓腹外侧区和网状结构内儿茶酚胺能神经元有些至下丘脑腹内侧核的投射,其中一部分儿茶酚胺能神经元参与了胃伤害性刺激的传导和调控。     

Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men

Hypo- or hyperthyroidism is associated with autonomic disorders. We studied Fos expression in the medullary dorsal motor nucleus of the vagus (DMV), nucleus tractus solitarii (NTS), and area postrema (AP) in four groups of rats with different thyroid states induced by a combination of drinking water and daily intraperitoneal injection for 1-4 wk: 1) tap water and vehicle; 2) 0.1% propylthiouracil (PTU) and vehicle; 3) PTU and thyroxine (T4; 2 microg/100 g); and 4) tap water and T4 (10 microg/100 g). The numbers of Fos immunoreactive (IR) positive neurons in the DMV, NTS, and AP were low in euthyroid rats but significantly higher in the 4-wk duration in hypothyroid rats, which were prevented by simultaneous T4 replacement. Hyperthyroidism had no effect on Fos expression in these areas. There were significant negative correlations between T4 levels and the numbers of Fos-IR-positive neurons in the DMV (r = -0.6388, P < 0.008), NTS (r = -0.6741, P < 0.003), and AP (r = -0.5622, P < 0.004). Double staining showed that Fos immunoreactivity in the DMV of hypothyroid rats was mostly localized in choline acetyltransferase-containing neurons. Thyroid hormone receptors alpha1 and beta2 were localized in the observed nuclei. These results indicate that thyroid hormone influences the DMV/NTS/AP neuronal activity, which may contribute to the vagal-related visceral disorders observed in hypothyroidism.     

Peripheral CRF activates myenteric neurons in the proximal colon through CRF(1) receptor in conscious rats

Corticotropin-releasing factor (CRF) injected peripherally induces clustered spike-burst activity in the proximal colon through CRF(1) receptors in rats. We investigated the effect of intraperitoneal CRF on proximal colon ganglionic myenteric cell activity in conscious rats using Fos immunohistochemistry on the colonic longitudinal muscle/myenteric plexus whole mount preparation. In vehicle-pretreated rats, there were only a few Fos immunoreactive (IR) cells per ganglion (1.2 +/- 0.6). CRF (10 microg/kg ip) induced Fos expression in 19.6 +/- 2.1 cells/ganglion. The CRF(1)/CRF(2) antagonist astressin (33 microg/kg ip) and the selective CRF(1) antagonist CP-154,526 (20 mg/kg sc) prevented intraperitoneal CRF-induced Fos expression in the proximal colon (number of Fos-IR cells/ganglion: 2.7 +/- 1.2 and 1.0 +/- 1.0, respectively), whereas atropine (1 mg/kg sc) had no effect. Double labeling of Fos with protein gene product 9.5 revealed the neuronal identity of activated cells that were encircled by varicose fibers immunoreactive to vesicular acetylcholine transporter. Fos immunoreactivity was mainly present in choline acetyltransferase-IR nerve cell bodies but not in the NADPH-diaphorase-positive cells. These results indicate that peripheral CRF activates myenteric cholinergic neurons in the proximal colon through CRF(1) receptor.     

Analogs of SR-141716A (Rimonabant) alter d-amphetamine-evoked [3H] dopamine overflow from preloaded striatal slices and amphetamine-induced hyperactivity

The CB(1) cannabinoid receptor antagonist SR-141716A (Rimonabant) markedly diminishes the behavioral effects of opiates and nicotine and has been an important tool to ascertain the role of cannabinoid receptors in drug addiction. The present goal was to determine the less-explored interaction of SR-141716A and d-amphetamine in neurochemical and behavioral assays. Additionally, the effect of the substituents and substitution patterns on the phenyl ring located at the 5 position of SR-141716A (4-chlorophenyl), and of the CB(1)/CB(2) cannabinoid receptor agonist WIN-55,212-2, was determined. SR-141716A, AM-251 (4-iodophenyl) and NIDA-41020 (4-methoxyphenyl) did not alter amphetamine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine. MRI-8273-30-1 (4-fluorophenyl; 0.1-10 microM) attenuated amphetamine (3 microM)-evoked [(3)H]overflow, and MRI-8273-59 (3,4-dichlorphenyl; 0.01-10 microM) augmented amphetamine (0.3-3 microM)-evoked [(3)H]overflow. WIN-55,212-2 was without effect. In a locomotor activity experiment, SR-141716A and MRI-8273-30-1 did not alter amphetamine-induced hyperactivity. However, MRI-8273-59 (1-3 mg/kg) dose-dependently attenuated amphetamine (1 mg/kg)-induced hyperactivity. The present results suggest that SR-141716A is less efficacious to alter amphetamine effects than its reported efficacy to diminish the effects of opiates and nicotine. Modification of the 5-phenyl position of SR-141716A affords compounds that do interact with amphetamine in vitro and in vivo.     

Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects

We investigated the role of the Ras/extracellular-regulated kinase (ERK) pathway in the development of tolerance to Delta(9)-tetrahydrocannabinol (THC)-induced reduction in spontaneous locomotor activity by a genetic (Ras-specific guanine nucleotide exchange factor (Ras-GRF1) knock-out mice) and pharmacological approach. Pre-treatment of wild-type mice with SL327 (50 mg/kg i.p.), a specific inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase of ERK, fully prevented the development of tolerance to THC-induced hypolocomotion. We investigated the impact of the inhibition of ERK activation on the biological processes involved in cannabinoid tolerance (receptor down-regulation and desensitization), by autoradiographic cannabinoid CB1 receptor and cannabinoid-stimulated [(35)S]GTPgammaS binding studies in subchronically treated mice (THC, 10 mg/kg s.c., twice a day for 5 days). In the caudate putamen and cerebellum of Ras-GRF1 knock-out mice and SL327 pre-treated wild-type mice, CB1 receptor down-regulation and desensitization did not occur, suggesting that ERK activation might account for CB1 receptor plasticity involved in the development of tolerance to THC hypolocomotor effect. In contrast, the hippocampus and prefrontal cortex showed CB1 receptor adaptations regardless of the genetic or pharmacological inhibition of the ERK pathway, suggesting regional variability in the cellular events underlying the altered CB1 receptor function. These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC-induced hypomotility.     

肾缺血引起大鼠儿茶酚胺神经元Fos表达

实验应用Fos蛋白和酪氨酸羟化酶（tyrosine hydroxylase,TH）的双重免疫组化方法,观察肾脏动脉阻断（renal artery occlusion,RAO）是否激活脑干中核团的儿荷酚胺能神经元。所得结果如下：（1）脑干中Fos样蛋白的基础性表达低;RAO可诱发孤束核（nucleus tractus solitarius,NTS）、最后区（area postrema,AP）、巨细胞旁外侧核（paragi-gantocellularis lateralis,PGL）和蓝斑（locus coeruleus,LC）核团中许多神经元显示Fos样免疫反应（Fos-like immunoreactivi-ty,FLI）。（2）NTS、AP、PGL和LC核团中含有较多的儿茶酚胺能神经元;RAO能激活其中的部分儿荷酚胺能神经元。（3）腺苷受体阻断剂8－苯茶碱可明显减弱RAO所致的上述效应。以上结果表明,肾脏短暂缺血能激活脑干内的一些神经核团以及其中的部分儿荷酚胺能神经元。此效应可能是肾缺血时腺苷释放作用于肾内腺苷受体后引起肾传入神经活动增加的结果。     

Synergistic interaction between CCK and leptin to regulate food intake

Leptin administered (either intracerebroventricularly, icv, or intraperitoneally, ip) acts in synergy with CCK to suppress food intake and body weight in lean mice or rats. The potentiating effect induced by the co-injection of ip CCK and leptin to inhibit food consumption in mice is mediated by the CCK-A receptor and capsaicin sensitive afferents. In vitro, studies in rats showed that a subset of gastric vagal afferent fibers responded to leptin injected directly into the gastric artery only after a prior intra-arterial CCK injection. Moreover, the tonic activity of gastric-related neurons in the nucleus tractus solitarius (NTS) increased when leptin was delivered into the gastric chamber of an in vitro stomach-brainstem preparation. CCK co-injected with leptin potentiated Fos expression selectively in the area postrema, NTS and paraventricular nucleus of the hypothalamus (PVN), which points to the PVN as part of the afferent and efferent limbs of the circuitry involved in the synergistic interaction between leptin and CCK. The dampening of CCK or leptin inhibitory action on ingestive behavior when either factor is not present or their receptors are non functional supports the notion that such leptin-CCK interaction may have a physiological relevance. These observations provide a mean through which leptin and CCK integrate short- and mid-term meal-related input signals into long-term control of energy balance.     

孤束核内微量注射乙酰胆碱对刺激兔下丘脑诱发期前收缩的影响

电刺激兔下丘脑乳头体及其周围区域诱发期前收缩(HSE)。电刺激一侧颈迷走神经中枢端,或电刺激延髓孤束核区域(NTS),均使HSE数减少。而电刺激延髓最后区、网状结构内2/3区域的背侧部以及三叉脊束核等区域对HSE数影响不大。NTS内微量注射乙酰胆碱,使HSE数减少。NTS内微量注射阿托品,可减弱刺激迷走神经对HSE的抑制作用。上述结果提示:电刺激颈迷走神经中枢端对HSE有抑制作用,此作用可能与延髓孤束核内乙酰胆碱的释放有关。     

The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.     

Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain

Delta9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa preparations, exerts its central effects mainly through the G-protein coupled receptor CB1, a component of the endocannabinoid system. Several in vitro and in vivo studies have reported neuroprotective effects of cannabinoids in excitotoxicity and neurodegeneration models. However, the intraneuronal signaling pathways activated in vivo by THC underlying its central effects remain poorly understood. We report that THC acute administration (10 mg/kg, i.p.) increases the phosphorylation of Akt in mouse hippocampus, striatum, and cerebellum. This phosphorylation was mediated by CB1 receptors as it was blocked by the selective CB1 antagonist rimonabant. Moreover, PI3K inhibition by wortmannin abrogated THC-induced phosphorylation of Akt, but blockade of extracellular signal-regulated protein kinases by SL327 did not modify this activation/phosphorylation of Akt. Moreover, administration of the dopaminergic D1 (SCH 23390) and D2 (raclopride) receptor antagonists did not block the activation of PI3K/Akt pathway induced in the striatum by cannabinoid receptor stimulation, suggesting that this effect is independent of the dopaminergic system. In addition, THC increased the phosphorylation of glycogen synthase kinase 3 beta. Therefore, activation of the PI3K/Akt/GSK-3 signaling pathway may be related to the in vivo neuroprotective properties attributed to cannabinoids.     

Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats

Enhanced intestinal transit due to lipopolysaccharide (LPS) is reversed by cannabinoid (CB)2 receptor agonists in vivo, but the site and mechanism of action are unknown. We have tested the hypothesis that CB2 receptors are expressed in the enteric nervous system and are activated in pathophysiological conditions. Tissues from either saline- or LPS-treated (2 h; 65 microg/kg ip) rats were processed for RT-PCR, Western blotting, and immunohistochemistry or were mounted in organ baths where electrical field stimulation was applied in the presence or absence of CB receptor agonists. Whereas the CB2 receptor agonist JWH133 did not affect the electrically evoked twitch response of the ileum under basal conditions, in the LPS-treated tissues JWH133 was able to reduce the enhanced contractile response in a concentration-dependent manner. Rat ileum expressed CB2 receptor mRNA and protein under physiological conditions, and this expression was not affected by LPS treatment. In the myenteric plexus, CB2 receptors were expressed on the majority of neurons, although not on those expressing nitric oxide synthase. LPS did not alter the distribution of CB2 receptor expression in the myenteric plexus. In vivo LPS treatment significantly increased Fos expression in both enteric glia and neurons. This enhanced expression was significantly attenuated by JWH133, whose action was reversed by the CB2 receptor antagonist AM630. Taking these facts together, we conclude that activation of CB2 receptors in the enteric nervous system of the gastrointestinal tract dampens endotoxin-induced enhanced intestinal contractility.     

A neutral CB1 receptor antagonist reduces weight gain in rat

Cannabinoid (CB)1 receptor inverse agonists inhibit food intake in animals and humans but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain, and emesis. Neutral antagonist and binding properties were confirmed in HEK-293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin-stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80 +/- 0.44 nM) in competitive binding assays with the CB1/2 agonist [3H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg/kg) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg/kg), a highly anorectic dose of AM4113 (10 mg/kg) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans, they could be developed into a new class of antiobesity agents.     

颈动脉注射辣椒素对脑干心血管相关核团一氧化氮合酶和Fos表达的影响

实验采用NADPH－d组化技术和Fos蛋白免疫组化技术相结合的方法,观察了颈动脉注射辣椒不时,大鼠脑干心血管相关核团内NOS和Fos蛋白的分布以及两者的共存关系。结果显示：（1）颈动脉注射辣椒不可诱发脑干中最后区（AP）、孤束核（NTS）、巨细胞旁外侧核（PGL）和蓝斑（LC）等多个部位Fos样免疫反应（FLI)神经元显著增加 中脑中央灰质（PAG）和中缝核群（RN）的FLI神经元无明显改变。（2）PGL和NTS内NO合成神经元以及PGL内双标神经元数量也明显增加,而AG和RN中NO合成神经元无明显变化,在LC和AP仅偶见或未见NO合成神经元。（3）预先应用辣椒素受体阻断剂钌红或NMDA受体阻断剂MK－801,则明显减弱辣椒素的上述效应,以上结果表明,颈动脉注射辣椒素可兴奋脑干心血管活动相关核团神经元,NO在脑干核团对辣椒素的反应中发挥间接的调制作用,辣椒素的效应由香草酸受体（辣椒素受体）介导并有谷氨酸参与。     

Neuronal activation of brain vagal-regulatory pathways and upper gut enteric plexuses by insulin hypoglycemia

Neuronal activation of brain vagal-regulatory nuclei and gastric/duodenal enteric plexuses in response to insulin (2 U/kg, 2 h) hypoglycemia was studied in rats. Insulin hypoglycemia significantly induced Fos expression in the paraventricular nucleus of the hypothalamus, locus coeruleus, dorsal motor nucleus of the vagus (DMN), and nucleus tractus solitarii (NTS), as well as in the gastric/duodenal myenteric/submucosal plexuses. A substantial number of insulin hypoglycemia-activated DMN and NTS neurons were choline acetyltransferase and tyrosine hydroxylase positive, respectively, whereas the activated enteric neurons included NADPH- and vasoactive intestinal peptide neurons. The numbers of Fos-positive cells in each above-named brain nucleus or in the gastric/duodenal myenteric plexus of insulin-treated rats were negatively correlated with serum glucose levels and significantly increased when glucose levels were lower than 80 mg/dl. Acute bilateral cervical vagotomy did not influence insulin hypoglycemia-induced Fos induction in the brain vagal-regulatory nuclei but completely and partially prevented this response in the gastric and duodenal enteric plexuses, respectively. These results revealed that brain-gut neurons regulating vagal outflow to the stomach/duodenum are sensitively responsive to insulin hypoglycemia.