U50,488H抑制中性粒细胞在大鼠缺血/再灌注心肌中的聚集和TNF-α生成

目的:观察К-阿片受体激活对大鼠心肌缺血/再灌注(MI/R)局部心肌中性粒细胞聚集的影响及其相关机制。方法:将60只成年健康SD大鼠随机分为假手术组、缺血/再灌注(I/R)生理盐水组、К-阿片受体激动剂(U50,488H)组、U50,488H+Nor-BNI组、U50,488H+Wortmannin组及U50,488H+L-精氨酸甲酯(L-NAME)组,每组9~10只大鼠。使心肌局部缺血30 min再灌注3 h后处死动物,检测大鼠心梗面积并按相应试剂盒提供方法检测血清肌酸激酶(CK)、心肌中髓过氧化物酶(MPO)活性、一氧化氮(NO)及心肌和血清中肿瘤坏死因子-α(TNF-α)的水平。结果:与I/R生理盐水组相比较,U50,488H组的心梗面积(P0.05)、血清CK活性(P0.05)、心肌MPO(P0.05)及心肌和血清TNF-α(P0.05)的水平明显下降,同时心肌中NO(P0.05)的水平上升;而К-阿片受体的选择性阻断剂(Nor-BNI)、PI3K的选择性抑制剂(Wortmannin)及NO合成酶(NOS)抑制剂(L-NAME)均可消除U50,488H的上述作用(P0.05)。结论:U50,488H可通过激活К-阿片受体,发挥对心脏的保护作用。U50,488H的保护作用可能与其激活PI3-激酶,增加心肌中NO的合成,减少中性粒细胞向I/R损伤心肌的聚集和MI/R诱导的TNF-α生成有关。     

к阿片受体介导的抗心律失常作用

目的:研究激动к阿片受体对大鼠心肌缺血性心律失常的影响. 方法:在结扎大鼠冠状动脉的同时,静脉注射选择性к阿片受体激动剂U50488H,观察其对大鼠心率(HR)、左心室内压(LVSP)和室性心律失常发生的影响;分离大鼠心室肌细胞,观察U50488H对细胞内钙和L-型钙电流的影响. 结果:心肌缺血后,大鼠HR无明显变化,LVSP 显著降低,心电图显示了缺血性改变和心律失常发生;心肌缺血并给予U50488H后,HR显著减慢,LVSP进一步降低,大鼠心肌缺血性心律失常的发生率以及心律失常评分明显降低.U50488H可明显降低心肌细胞的钙瞬变,并能显著降低L-型钙电流.U50488H的作用均可被选择性к阿片受体阻断剂nor-BNI阻断.结论:激动к阿片受体可减少大鼠心肌缺血性心律失常的发生,其机制可能与其抑制L-型钙通道和细胞内钙有关.     

κ阿片受体介导的抗心律失常作用

目的：研究激动κ阿片受体对大鼠心肌缺血性心律失常的影响。方法：在结扎大鼠冠状动脉的同时，静脉注射选择性κ阿片受体激动剂U50488H，观察其对大鼠心率(HR)、左心室内压(LVSP)和室性心律失常发生的影响；分离大鼠心室肌细胞，观察U50488H对细胞内钙和L—型钙电流的影响。结果：心肌缺血后，大鼠HR无明显变化，LVSP显著降低，心电图显示了缺血性改变和心律失常发生；心肌缺血并给予U50488H后，HR显著减慢，LVSP进一步降低，大鼠心肌缺血性心律失常的发生率以及心律失常评分明显降低。U50488H可明显降低心肌细胞的钙瞬变，并能显著降低L—型钙电流。U50488H的作用均可被选择性κ阿片受体阻断剂nor—BNI阻断。结论：激动κ阿片受体可减少大鼠心肌缺血性心律失常的发生，其机制可能与其抑制L一型钙通道和细胞内钙有关。     

κ-阿片受体激动剂U50488H对内皮素-1所致大鼠室性心律失常的影响

目的:研究κ-阿片受体选择性激动剂U50488H是否可通过调节内皮素-1(ET-1)表达的水平,进而影响c-Src蛋白酪氨酸激酶(PTK)的表达以实现抗心律失常的作用。方法:将42只大鼠随机分为7组(每组6只):正常对照组、U50488H组、U50488H+nor-BNI组、nor-BNI组、ET-1组、ET-1+U50488H组及ET-1+U50488H+nor-BNI组。左心室及股动脉插管观测大鼠心率(HR)、动脉压(ABP)、左心室内压(LVP)及心脏收缩和舒张功能(±LVdp/dtmax)等血流动力学指标,并计算大鼠室性心律失常的发生情况和大鼠的死亡率。实时荧光定量PCR检测ET-1及ET-1受体(ETRA)mRNA表达;Western blot测定ETRA及下游分子c-Src PTK的表达水平。结果:U50488H可显著抑制ET-1所致大鼠ABP、LVP以及心脏收缩、舒张功能的升高,并可显著降低ET-1所致大鼠室性心律失常的发生率和死亡率(P<0.01),以及抑制心肌ET-1 mRNA的水平(P<0.01)。给予ET-1后,磷酸化(P)-c-Src PTK的表达水平升高,U50488H可显著降低c-Src PTK的水平以及ET-1引起的P-c-Src PTK表达的水平(P<0.05),此作用可被κ-阿片受体阻断剂nor-BNI所阻断。结论:κ-阿片受体选择性激动剂U50488H可抑制ET-1所致大鼠室性心律失常发生。该作用可能与抑制ET-1及其下游分子c-Src PTK的表达有关。     

U50488对大鼠离体心心律及心肌细胞内游离钙的影响

观察选择性Kappa(κ)阿片受体激动剂U50488对大鼠离体心心律及心肌细胞内游离钙([Ca2+]i)的作用.结果显示:U50488可诱发心律失常并增加静息心肌细胞[Ca2+]i,U50488诱发心律失常及增加心肌细胞[Ca2+]i的作用可被选择性κ阿片受体拮抗剂Nor-binaltorphimine(Nor-BNI)及选择性磷酯酶C抑制剂U73122、新霉素及链霉素所阻断.表明心脏κ阿片受体激活所致的心律失常是由于磷酸肌醇信号传导通路激活引起心肌细胞[Ca2+]i增多所致.     

κ-阿片受体激动剂U50,488H抑制缺血/再灌注心肌线粒体分裂的作用及机制

目的研究外源性κ-阿片受体激动剂U50,488H对缺血/再灌注心肌线粒体分裂的影响及机制。方法将SD大鼠随机分为6组:假手术（Sham）组，心肌缺血/再灌注（MI/R）组，MI/R+κ-阿片受体激动剂U50,488H（MI/R+U）组，MI/R+κ-阿片受体阻断剂nor-BNI+U50,488H（MI/R+N+U）组，MI/R+磷脂酰激醇3-激酶（pi 3-kinases，PI3K）抑制剂wortmannin+U50,488H（MI/R+W+U）组，MI/R+蛋白激酶B（protein kinase B, Akt）抑制剂MK2206+U50,488H（MI/R+M+U）组。血清肌酸激酶（creatine kinase, CK）试剂盒检测血清CK水平；三苯基氯化四氮唑（triphenyte-trazoliumchloride, TTC）-伊文氏蓝双染检测心肌梗死面积；Western blotting检测细胞内磷酸化PI3K、磷酸化Akt（Ser 473）、磷酸化线粒体动力学分裂相关蛋白（dynamin-related protein, Drp）1（Ser 637）的表达；透射电镜观察线粒体形态。结果与Sham组相比，MI/R组血清CK水平明显升高（P<0.01），出现明显的心肌梗死（P<0.01），磷酸化PI3K、磷酸化Akt表达增加（P<0.05），磷酸化Drp1表达降低（P<0.01），线粒体分裂明显增加（P<0.01）；与MI/R组相比，MI/R+U组血清CK水平明显降低（P<0.01），心肌梗死面积减小 （P<0.01），磷酸化PI3K、磷酸化Akt和磷酸化Drp1的表达显著增加（P<0.01），线粒体分裂减少（P<0.01）。给予nor-BNI、wortmannin或MK2206后，U50,488H的上述作用均被阻断。结论缺血/再灌注可引起心肌损伤和线粒体分裂增加，κ-阿片受体激活后通过PI3K-Akt通路使Drp1磷酸化增加，抑制缺血/再灌注心肌的线粒体分裂，减轻心肌损伤。     

急性心肌缺血再灌注犬心肌组织NF-κB的表达与瑞芬太尼的干预作用

目的 观察急性心肌缺血再灌注犬心肌组织NF-κB的表达及瑞芬太尼预处理对NF-κB表达的影响.方法 健康杂种犬18只,随机分为:假手术组(S组)、缺血再灌注组(I/R组)、瑞芬太尼预处理组(RPC组).S组犬开胸后在冠状动脉左前降支下穿线不结扎;I/R组犬开胸后结扎冠状动脉左前降支,缺血30 min再灌注2 h;RPC组为缺血前以1 pg／(kg·min)微泵输注瑞芬太尼30 min进行预处理,余同I/R组.再灌注2 h时处死犬取心肌组织,免疫组化法检测心肌组织NF-κB的表达情况.结果 I/R组、RPC组与S组相比,心肌组织NF-κB含量显著升高(P<0.05),RPC组与I/R组比较,心肌组织NF-κB的表达降低(P<0.05).结论 急性心肌缺血再灌注犬心肌组织NF-κB的表达显著增强,瑞芬太尼预处理可降低再灌注2 h时心肌组织NF-κB的表达.     

U50 488H预处理大鼠诱导的延迟性心脏保护效应及其机制

目的 :trans- （± ） - 3,4 - dichloro- N- methyl- N - [2 - （1- pyrrolidinyl） cyclohexyl]- benzeneacetam ide （U 5 0 4 88H）是κ阿片受体的选择性激动剂。实验观察静脉注射 U 5 0 4 88H （10 mg/ kg） 2 4 h后对心脏的延迟性保护作用及其细胞内机制。方法 :1采用离体灌流的大鼠心脏模型 ,通过局部缺血 /再灌注 ,以心脏梗死面积作为心脏损伤的判定标准 ,观察 U 5 0 4 88H预处理 （U P）对心脏的延迟性保护作用。 2采用分离的大鼠心肌细胞模型 ,通过代谢抑制（metabolic inhibition,MI） ,观察 UP对心肌细胞内静息 Ca2 + 和电诱导 Ca2 + 瞬变的影响。结果 :1U P可显著降低心脏梗死面积 ;2 U P的大鼠心肌细胞在 MI时 ,心肌细胞内静息 Ca2 + 的升高程度较对照组显著降低 ;3U P的大鼠心肌细胞在 MI时 ,心肌细胞电诱导 Ca2 + 瞬变的降低程度较对照组显著减少。上述作用均可被 U P前 10 min腹腔注射κ阿片受体的选择性阻断剂 nor- binaltorphim ine （10 m g/ kg）阻断。结论 ::U 5 0 4 88H可通过刺激κ阿片受体产生延迟性的心脏保护作用 ,此作用与心肌细胞内的 Ca2 + 稳态的调节有关。     

阿片受体k亚型在大鼠心肌细胞热应激反应中的作用

目的：U50488H是阿片肽受体k亚型的选择性激动剂,本实验研究U50488H预处理是否可增强心对热应激的耐受性,同时观察与热休克蛋白70及90表达的关系。方法：采用分离的大鼠心肌细胞作为研究对象,以心肌细胞释放乳酸脱氢酶（LDH）的多少反映其损伤程度并用Western blot分析热休克蛋白表达的变化。结果：在5－30μmol/L浓度范围内,U50488H预处理30min剂量依赖性的减低心肌细胞热应激后LDH的释放。同时热休克蛋白70和90的表达明显增加。结论：U50488H激活阿片受体后具有保护心肌细胞的作用,其保护机制可能与调节热休克蛋白的表达有关。     

U50488H对缺血/再灌注心脏的保护作用

研究已证实,κ阿片受体选择性激动剂U50488H可明显降低缺血/再灌注(I/R)后的心肌细胞凋亡数、心肌梗死面积,降低心律失常的发生率,改善心脏及冠脉微循环的功能。与吗啡等传统阿片类药物相比较,U50488H有较强的镇痛、降压及心脏保护作用,其相关作用机制日益成为近年来研究的热点之一。现就U50488H对I/R心脏的保护作用的最新进展进行综述。     

The Effect of U50488 on the Cardiac Rhythm and Intracellular Calcium in the Rat Heart.

The effect of U50488, a selective K-opioid receptor agonist, on cardiac rhythm in the isolated perfused rat heart and intracellular calcium ([Ca2 ] i) in the single ventricular myocyte were studied. The results showed that U50488 can induce arrhythmias dose-dependently in the isolated perfused rat heart and increase [ Ca2 ] i in the single ventricular myocyte. The effect of U50488 can be blocked by a selectivek-receptor antagonist, nor-binaltorphimine. The arrhythmogenic effects and the increase of [ Ca2 ]i induced by U50488 were blocked by U73122, neomycin and streptomycin, which are selective phospolipase C inhibitors, but not by U73433, the inactive structural analog of U73122. These results demonstrated that the arrhythmogenic effect of cardiac K-receptor is due to activation of phosphoinositol/Ca2 pathway.     

阿司匹林对心肌晚期缺血预适应的干预作用

目的:观察环氧化酶-2(COX-2)在正常心肌中表达的部位及表达量,并探索不同剂量阿司匹林作用于心肌晚期缺血预适应(DPC)后,对心肌COX-2蛋白的表达及心脏超微结构的影响。方法:采用结扎兔冠状动脉左前降支建立DPC模型。随机分为5组,分别为正常对照组,DPC组,小、中、大剂量组(阿司匹林5mg/kg、12mg/kg、20mg/kg)。实验后48h取心肌组织,应用免疫组化法、蛋白质免疫印迹法测定COX-2蛋白表达,应用电镜观察心肌超微结构的变化。结果:兔DPC组心肌COX-2蛋白表达明显高于正常对照组水平,差异有统计学意义(P<0·05);小、中剂量组对COX-2蛋白表达影响较小,差异无统计学意义(P>0·05),电镜观察心肌超微结构无明显变化;大剂量组对COX-2蛋白表达明显降低,差异有统计学意义(P<0·05),电镜证实大剂量阿司匹林对心肌超微结构的损伤加重。结论:通过缺血、缺氧可刺激心肌COX-2蛋白表达增加,大剂量阿司匹林可抑制COX-2蛋白表达,可能导致心肌损伤加重,故临床上避免在心肌DPC过程中接受大剂量阿司匹林治疗。     

远隔预处理和后处理对兔急性心肌缺血再灌注损伤的作用

目的探讨远隔预处理和后处理是否具有减轻兔心肌缺血再灌注损伤的作用及其机制。方法新西兰大白兔40只，随机平均分为4组：对照组、心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组，分组进行干预。测定血浆磷酸肌酸激酶（CK）和丙二醛（MDA）活性及心肌梗死面积并检测组织髓过氧化物酶（MPO）活性。结果心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组心肌梗死面积、再灌注末MDA活性、缺血组织MPO活性均明显低于对照组（均P〈0．01）。结论远隔预处理和后处理均有显著的心脏保护作用，其作用可能与减轻活性氧的损伤及抗氧化作用加强有关。     

Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning”

ObjectivesThis study examined the changes in myocardial energy metabolism during myocardial ischemia after “remote preconditioning” and investigated the involvement of adenosine receptors in the mechanisms of this effect.BackgroundRecent studies have indicated that a brief period of ischemia and reperfusion (ischemic preconditioning, PC) in a remote organ reduces myocardial infarct size (IS) protecting against subsequent sustained myocardial ischemia. However, the mechanisms of “remote PC” remain unclear. We assessed myocardial energy metabolism during sustained myocardial ischemia and reperfusion after renal PC (RPC), in comparison with that after myocardial PC (MPC) in open-chest rabbits. It has been established that adenosine receptors are involved in the mechanisms of MPC.MethodsRabbits that had been anesthetized with halothane were divided into six groups. The control (CNT) group underwent 40-min coronary occlusion followed by 120 min reperfusion. Before the procedure, the MPC group underwent an additional protocol of 5 min coronary artery occlusion and 20 min reperfusion, and the RPC group received a 10 min episode of renal artery occlusion and 20 min reperfusion. In additional experimental groups, 8 sulfophenyltheophylline (SPT, 10 mg/kg), an adenosine receptor inhibitor, was intravenously injected before the 40 min myocardial ischemia (SPT, MPC + SPT and RPC + SPT groups, respectively). Myocardial levels of phosphocreatine (PCr), ATP and intracellular pH (pHi) were measured by ³¹P-NMR spectroscopy.ResultsRPC and MPC delayed the decreases in ATP levels, preserved pHi during 40-min myocardial ischemia and resulted in better recovery of ATP and PCr during 120 min reperfusion compared with the controls. SPT abolished the improvement in myocardial energy metabolism and the reduction in myocardial IS caused by MPC or RPC. Myocardial IS in the CNT (n = 8), MPC (n = 9), RPC (n = 9), SPT (n = 6), MPC + SPT (n = 8) and RPC + SPT (n = 8) groups averaged 42.8 ± 3.5%, 18.2 ± 1.8%1, 19.6 ± 1.3%1, 44.9 ± 5.0%, 35.6 ± 2.7% and 34.8 ± 3.6% of the area at risk (1p < 0.05 vs. CNT), respectively.ConclusionsPC in a remote organ, similar to MPC, improved myocardial energy metabolism during ischemia and reperfusion and reduced IS in vivo by an adenosine-dependent mechanism in rabbits.     

Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning.

OBJECTIVE: The aims were to examine the role of adenosine receptors in the mechanism of preconditioning in a chronic rabbit model of myocardial infarction; to assess whether the preconditioning effect is blocked by an adenosine receptor antagonist, 8-phenyltheophylline; and to determine whether an adenosine A1 receptor agonist, R(-)N6-2-phenylisopropyl adenosine (R-PIA), mimics infarct size limitation by preconditioning. METHODS: Myocardial infarction was induced in male rabbits by occlusion of the left coronary artery for 30 min, which was followed by 72 h reperfusion. Before the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) untreated control; (2) intravenous injection of 8-phenyltheophylline; (3) preconditioning with 5 min ischaemia; (4) pretreatment with 8-phenyltheophylline plus preconditioning; (5) intravenous injection of R-PIA; or (6) R-PIA plus atrial pacing (240.min-1). Infarct size and area at risk were determined by histology and fluorescent particles, respectively. RESULTS: Preconditioning significantly limited infarct size, normalised as a percent of area at risk (%IS/AR), to 19.2 (SEM 2.3)% v control value of 46.5(2.8)%. 8-Phenyltheophylline alone did not modify the %IS/AR, but its injection before preconditioning attenuated the preconditioning effect such that IS/AR = 34.4(2.5)%. While R-PIA did not achieve statistically significant myocardial salvage, R-PIA plus atrial pacing limited infarct size to 33.7(3.0)% (p<0.05 v control). The R-PIA group had severe hypotension and their infarct sizes were inversely correlated with diastolic blood pressure at reperfusion. There was no such correlation in the R-PIA plus pacing group in which bradycardia and hypotension induced by R-PIA were attenuated by atrial pacing. CONCLUSIONS: The infarct size limiting effect of preconditioning was attenuated by 8-phenyltheophylline, and pretreatment with R-PIA was able to limit myocardial infarct size when severe hypotension was avoided by atrial pacing. These findings suggest that adenosine receptor activation plays a crucial role in the mechanism of preconditioning.     

Kappa opioid receptor agonists differentially inhibit two classes of rat spinal neurons excited by colorectal distention.

BACKGROUND & AIMS: Quantitative neurophysiological studies have identified the presence of at least 2 spinal neuronal populations (abrupt and sustained) that are excited by the noxious visceral stimulus colorectal distention. This study examined the effects of the kappa opioid receptor agonists fedotozine and U50488H on the activity of these neurons. METHODS: In decerebrate, cervical spinal cord-transected male rats, the lumbosacral spinal cord was exposed by a laminectomy. Dorsal horn neurons showing excitatory responses to colorectal distention (80 mm Hg, 20 seconds) were identified using microelectrodes. Cumulative doses of fedotozine and U50488H were administered intravenously or intrathecally, and antagonists were used. RESULTS: Intravenous fedotozine and U50488H dose-dependently inhibited the evoked activity of sustained neurons. This inhibition was partially reversed by the kappa opioid antagonist norbinaltorphimine. The same agents had insignificant effects on the evoked activity of abrupt neurons. Fedotozine inhibited spontaneous activity of both abrupt and sustained neurons. Intrathecally administered U50488H had no effect on abrupt or sustained neurons, but intrathecally administered fedotozine inhibited the evoked and spontaneous activity of both groups. CONCLUSIONS: Kappa opioid receptor agonists acting peripherally had differential effects on 2 spinal neuronal populations responsive to colorectal distention. Fedotozine had additional inhibitory effects acting within the spinal cord.     

缺血预适应对高血脂动脉硬化兔心肌的影响

目的研究缺血预适应(IP)对高血脂动脉硬化兔心肌的影响。方法用高胆固醇饲料喂养家兔,血总胆固醇≥15mmol/L,29只高血脂兔分为三组,采用结扎/开放左冠状动脉前降支(LDADC)的方法,给予不同时间和强度的缺血预处理:无缺血预处理组(HR1);缺血预处理组(HR2);多次及延长缺血预处理组(HR3),24只正常血脂兔也分为三组(NR1,NR2,NR3),实验方法与上述各组相同。缺血预处理后阻断冠状动脉30min,再灌注30min,给予程序电刺激,测定心室颤动阈(VFT)。心肌切片氯化硝基四氮唑蓝染色(NBT),判断心肌梗死面积(IS)。结果IP对正常兔心肌有保护作用:NR2、NR3组与NR1组相比,IS缩小,(P<0.01);VFT增高(P<0.05);对高血脂兔无作用(P>0.05)。增加缺血次数,延长缺血时间,对正常血脂兔,保护作用无改变(P>0.05);但加重高血脂兔后续缺血的损害:IS增加(P<0.01);VFT降低(P<0.05)。结论缺血预处理的保护作用与心肌的状态有关。对高血脂、动脉硬化兔心肌,缺血预处理的保护作用可能消失。     

后肢远程预处理对心肌缺血再灌注与心交感神经损伤的影响

目的：后肢远程缺血预处理对急性心肌缺血再灌注与心交感神经损伤影响的实验研究。方法：20只雄性新西兰大白兔随机被均分成两组：对照组及远程缺血预处理（RIPC）组。两组均制作心肌缺血模型。RIPC组在心肌缺血前行双后肢短暂缺血预处理2次（充气式压力止血带环扎双后肢腘窝上1／3,压力26．6kPa,每次10min,间隔10min）,最后一次后肢缺血预处理后再灌注60min制作急性心肌缺血模型。其方法为：冠状动脉左前降支完全闭塞45min,于松开结扎圈再灌注2、4h时,分别以碘-间位碘代苄胍（^131-MIBG）、^99m锝-甲氧基异丁基异腈（^99mTc-MIBI）双核素作放射自显影,其后以美蓝、氯化四唑（TTC）作组织染色,分别确定心肌危险梗塞灶与实际梗塞灶。结果：再灌注4h后,预处理组危险梗塞灶与实际梗塞灶均小于对照组（P〈0．01）。^131I-MIBG及^99m～Tc-M1BI自显影在同一区域摄取存在差异性,两组^131I-MIBG显影缺损面积（40．8土3．2）％．均显著比^99mTc-MIBI显影缺损及实际梗塞灶大（P〈0．05）。结论：远程预处理能有效阻断心肌缺血再灌注对交感神经损伤的作用;利用交感神经显影剂MIBG显影能客观监测心肌梗塞病变范围和程度,评价远程预处理的心肌保护效应。     

Effect of the opioid kappa-receptor agonist U50488H on the secretion of arginine vasopressin. Study on the mechanism of U50488H-induced diuresis

The effect of U50488H, a potent opioid kappa-receptor agonist, was investigated on the urine volume and on the secretion of arginine vasopressin (AVP) in response to dehydration or hyperosmolar or hypovolemic stimulation in conscious rats. This agonist markedly increased the urine volume in normally hydrated rats and suppressed plasma AVP in a dose-dependent manner in rats given hyperosmolar saline. This suppression of plasma AVP was completely reversed by concurrent injection of naloxone. U50488H also inhibited the release of AVP in dehydrated or hypovolemic rats. These findings indicate that the diuresis induced by U50488H is mainly caused by the suppression of plasma AVP. They also suggest that the kappa-opioid receptor plays an important role in regulating the secretion of AVP.