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1.
The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions. 相似文献
2.
The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was examined on opioid-induced antinociception in the tail flick test. Swiss Webster mice were injected with ACEA-1328 either alone or in combination with morphine or (±)-trans-U-50488 methanesulfonate (U50,488H), a μ- and a κ-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED50of approximately 45 mg kg−1. Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagonist, while not modifying the effect of ACEA-1328, did block the augmentation, suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762), a selective NMDA receptor/glycine site antagonist, also showed enhancement of the antinociceptive effect of morphine and U50,488H. However, concurrent administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not alter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor. 相似文献
3.
本研究观察了大鼠接受慢性吗啡处理过程中,心脏中κ受体结合位点的变化及其对κ激动剂US50488致心律失常作用的反应。结果表明,在慢性吗啡处理过程中,心脏κ结合位点数目逐渐增加,至d10超过对照一倍以上;同时在慢性处理d8和d10,鼠心对U50488H的致心律失常效应出现明显的耐受。撤药后2d,鼠心κ结合位点与其对κ激动剂的效应回复至对照水平,结果提示,大鼠的μ阿片耐受可引起心脏κ受体兴奋后反应的改变。 相似文献
4.
目的:探讨百日咳毒素(PTX)敏感的G蛋白是否介导κ阿片激动剂的心脏效应。方法:应用离体大鼠心脏Langendorf灌流模型观察κ阿片激动剂U50488H的心脏作用并探讨其可能机制。结果:研究结果表明,U50488H可导致心律失常、降低心率、心肌收缩力量和冠脉流量;MR2266和百日咳毒素(PTX)预处理后,可取消U50488H的致心律失常作用,但不能取消其降低心肌收缩力量和冠脉流量的作用。结论:结果提示κ阿片激动剂的致心律失常作用涉及PTX敏感的G蛋白机制。 相似文献
5.
A number of investigators have shown that sex plays an important role in the analgesic effects of opioids. Typically, the antinociceptive responsiveness to mu opioid agonists such as morphine is greater in male than in female rats. The effect of sex on kappa opioid analgesia is less known. The present study was conducted to examine sex-related differences in responsiveness to oxycodone (putative kappa/mu opioid agonist). This information is important since oxycodone is widely used clinically for treatment of pain. The present results indicated that oxycodone had a greater antinociceptive response in female rats compared to male rats. This sex specific responsiveness to oxycodone, however, was lost with chronic administration. The greater antinociception in female rats was even more prominent with U50,488H (selective kappa agonist). Further, low (subanalgesic) doses of oxycodone and U50,488H enhanced the sensitivity to pain (hyperalgesia) to a greater extent in male than in female rats. This is in contrast to the previously shown greater hyperalgesic effect of subanalgesic doses of the mu opioid agonist, morphine, in female than in male rats. The present findings suggest that sexual dimorphism in the effect of opioids is related to the opioid receptors on which they predominately act. 相似文献
6.
U-50488 [trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)-benzeneacetamide] is a structurally novel analgesic reported to have specific kappa opioid receptor agonist properties. Potent antinociceptive activity was demonstrated in rhesus monkeys and the effect was reversed by naloxone. The overt behavioral effects of U-50488 at supra-analgesic doses more closely resembled those of ethylketocyclazocine (EKC) than morphine. In monkeys trained to discriminate a 10-g/kg dose of EKC from saline, the stimulus effects generalized completely to U-50488 and other kappa agonists (e.g., bremazocine, cyclazocine), but not to the pure mu agonists. Like the other kappa agonists, U-50488 produced diuresis in monkeys by a naloxone-sensitive mechanism. In drug-naive rats offered continuous opportunity to self-administer drugs IV, most rats self-administered morphine or EKC, but none of the rats self-administered U-50488 at a rate above that of a group offered saline. Rats with continuous IV infusion of U-50488 for 3 weeks exhibited few abstinence signs and no weight loss when challenged with an injection of naloxone or after abrupt cessation of drug infusion. These experimental results support the previous reports in mice that U-50488 is a very selective kappa opioid agonist in rats and rhesus monkeys. 相似文献
7.
Previous research has demonstrated that voluntary exercise is associated with a reduction in mu-opioid-induced antinociception. To determine if the effects of voluntary exercise on opioid-induced antinociception were limited to drugs that affect the mu opioid receptor or were more general, the analgesic effects of the kappa opioid agonist U50,488H were compared in active and sedentary rats. Eight adult male Long-Evans rats were housed in standard hanging cages and eight in cages with attached running wheels for 20 days prior to antinociceptive testing. Pain thresholds were determined using a tail-flick procedure, and antinociception was expressed as percent maximal possible effect (%MPE). In the first study, U50,488H was administered in a cumulative dosing procedure (5.0, 10.0, 20.0 mg/kg). Tail-flick latencies were measured immediately prior to and 30 min following each injection. In the second study, the time course of U50,488H effects was examined in animals from the first experiment. Tail-flick latencies were measured immediately prior to and 30, 60, and 90 min following 10.0 mg/kg U50,488H. In the first study, U50,488H produced significant antinociception in both groups of rats. However, antinociceptive responses were significantly reduced for rats given access to running wheels relative to inactive rats. In the second study, antinociceptive responses to U50,488H continued for 90 min. Again, antinociceptive responses were lower for rats given access to running wheels relative to inactive rats. These results indicate that long-term voluntary exercise decreases the antinociceptive properties of the kappa agonist U50,488H, as well as the mu agonist morphine. 相似文献
8.
The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H. 相似文献
9.
Hamabe W Yamane H Harada S Tokuyama S 《The Journal of pharmacy and pharmacology》2008,60(9):1183-1188
Analgesic tolerance to morphine can develop from long-term use of this drug for the treatment of pain. Many reports have shown that stimulation of the kappa opioid receptor (KOR) suppresses development of analgesic tolerance to morphine. Here, we studied the KOR-mediated inhibition of morphine tolerance during repeated morphine treatment, with a focus on desensitization of the receptor. The development of analgesic tolerance to morphine during repeated morphine administration (10 mg kg(-1) s.c.) was completely suppressed by U-50488H (2 mg kg(-1) i.p.), a KOR agonist. The decrease in [35S] GTPgammaS binding activity stimulated by the mu opioid receptor (MOR) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) was also significantly inhibited by U-50488H. These results indicate that stimulation of KOR caused by repeated morphine treatment either inhibits MOR desensitization or accelerates recycling of MOR on the cell surface, thereby suppressing morphine tolerance. Furthermore, we found that activity of protein kinase C (PKC) was significantly decreased in mice treated with both U-50488H and morphine. These results suggest that the mechanisms underlying KOR-mediated inhibition of analgesic tolerance to morphine may be partly due to suppression of PKC activation and prevention of receptor desensitization. 相似文献
10.
Pierre Broqua Joseph G Wettstein Marie-Noëlle Rocher Pierre J.M Rivière Svein G Dahl 《European neuropsychopharmacology》1998,8(4):415-266
Fedotozine is a kappa opioid receptor agonist having antinociceptive properties but devoid of diuretic effects. The aim of the study was to evaluate the discriminative stimulus effects of fedotozine at doses previously reported to produce maximal effects in in vivo assays measuring kappa-mediated analgesia. By using a two-lever drug discrimination task, two groups of rats were trained to discriminate either a 3 mg/kg i.p. dose of the kappa opioid agonist, U50,488, or a 5 mg/kg i.p. dose of the mu opioid agonist, morphine, from saline. Once trained, rats were used to conduct tests of stimulus generalization with morphine, U50,488 and fedotozine along with another kappa agonist, CI-977, and another mu agonist, fentanyl. The stimulus effect of U50,488 was shared by CI-977 but not by morphine. Conversely, the stimulus effect of morphine was shared by fentanyl but not by U50,488. Fedotozine (1–10 mg/kg) failed to substitute to either U50,488 or morphine. These results indicate that, when administered at doses fully effective in producing antinociception, the interoceptive stimulus effects of fedotozine, if any, can be distinguished from those produced by U50,488 and morphine. 相似文献
11.
Suzuki Y Goto K Shiizaki K Omiya Y Ishige A Komatsu Y Kamei J 《The Journal of pharmacy and pharmacology》2001,53(4):521-526
We compared the antinociceptive activity of a kappa-opioid agonist, U-50488H, in streptozotocin-induced diabetic mice with that in non-diabetic mice. Subcutaneously administered U-50488H (3 and 10 mg kg(-1)) showed a more potent antinociceptive effect, as evaluated by the tail-pressure method, in diabetic mice than in non-diabetic mice. Increased antinociceptive activity of U-50488H observed in diabetic mice was also observed in mice given U-50488H intrathecally (3 and 10 microg). However, there were no differences observed between diabetic and non-diabetic mice given U-50488H intracerebroventricularly (3 and 10 microg). Although the antinociceptive effect of U-50488H (3 mg kg(-1), s.c.) in non-diabetic mice was increased by treatment with PD135158 (100 ng, i.c.v.), a cholecystokininB (CCKB) antagonist, the antinociceptive activity of U-50488H which was enhanced in diabetic mice was not influenced by PD135158. Moreover, the increased antinociceptive activity of U-50488H (3 mg kg(-1), s.c.) in diabetic mice diminished when desulfated octapeptide of cholecystokinin (3-100 ng, i.c.v.), a CCKB agonist, was administered. These results suggested that diabetic mice were selectively hyper-responsive to spinal kappa-opioid receptor-mediated antinociception. The function of the analgesia inhibitory system in which cholecystokinin is used as a transmitter might be diminished in diabetic mice. 相似文献
12.
目的探讨κ阿片受体在血管紧张素Ⅱ诱导内皮细胞产生白介素-6和白介素-8中的作用。方法整体实验观察大鼠静脉注射U50488H(1.5 mg.kg-1)后血中AngⅡ水平的变化;体外培养人脐静脉内皮细胞,分为对照组、AngⅡ组、AngⅡ+U50488H组,AngⅡ+U50488H+nor-BNI(κ阿片受体阻断剂)组。分别用磷酸盐缓冲溶液、AngⅡ(10-9~10-5mol.L-1)或提前给予κ阿片受体激动剂或(和)阻断剂诱导0~24 h,收集0、3、6、12、24 h等时间点的细胞培养液,采用酶联免疫吸附法分别检测细胞培养液IL-6和IL-8水平。结果静脉注射U50488H可明显降低血中AngⅡ的水平,该作用可被nor-BNI(2 mg.kg-1)所阻断。AngⅡ可浓度和时间依赖性诱导内皮细胞产生释放IL-6和IL-8,提前给予U50488H(10-5mol.L-1)可明显抑制AngⅡ诱导内皮细胞产生释放IL-6和IL-8。而nor-BNI(10-5mol.L-1)本身没有任何作用但可完全阻断U50488H的上述作用。结论 U50488H可通过下调AngⅡ水平和抑制AngⅡ的作用来减少内皮细胞产生IL-6和IL-8,表明κ阿片受体可能在抗炎中具有一定调节作用。 相似文献
13.
Functional changes in opioid receptors involved in analgesia of repeated cold stress (RCS)-loaded mice were investigated. The antinociceptive potency of morphine (4 mg/kg, PO) was not affected in normal mice by norbinaltorphimine (10 mg/kg, SC), but treatment with this agent resulted in a lower level of morphine-induced antinociception in RCS-loaded animals. The antinociceptive activity of U-50488H (3 mg/kg, SC) was increased in RCS-loaded mice. In contrast to hypersensitivity to U-50488H (1 and 10 microg, IT) noted in RCS-loaded mice, the antinociception induced by DAMGO (0.1 and 1 microg, ICV) was reduced compared to that of normal animals. Diazepam (1 mg/kg/day SC) was given during RCS loading, and this agent prevented the development of hyperalgesia and the decrease in the antinociceptive activity of DAMGO (1 microg, ICV) in RCS-loaded mice, but there was no effect on the enhancement of the antinociceptive potency of U-50488H (10 microg, IT). These results indicate that the RCS-loaded mice were hyposensitive to supraspinal mu-opioid receptor-mediated antinociception, whereas their antinociceptive activities through kappa-opioid receptor in the spinal cord were increased. Hypofunction of the supraspinal mu-opioid receptor due to anxiety may explain the mechanism involved in the lowering of the nociceptive threshold in RCS-loaded animals. 相似文献
14.
Centrally-administered opioid peptides produce elevations in levels of catecholamines in plasma in conscious rats. To investigate the opioid receptor involved in mediating this response, morphine (3.5-105 nmol), [D-Ala2-D-Leu5]enkephalin (DADL, 1.05-35 nmol) and U50, 488H (35-1160 nmol), relatively selective ligands for the mu, delta and kappa receptors respectively, were injected intracerebroventricularly into conscious rats and the levels of catecholamines in plasma determined at the peak of the response. Each agonist produced dose-dependent elevations in levels of noradrenaline and adrenaline, the order of potency being DADL approximately equal to morphine greater than U50,488H. These results exclude involvement of the kappa receptor but do not distinguish between an effect mediated by a mu or delta receptor. The responses to morphine were blocked in the presence of 300 nmol naloxone but were not altered by 41.5 nmol RX 781094, a selective alpha 2-adrenoceptor antagonist. The elevation in levels of adrenaline in plasma produced by small doses of the agonists was not related to behavioural changes. 相似文献
15.
Ishihara S Tsuchiya S Horie S Murayama T Watanabe K 《European journal of pharmacology》2001,418(3):187-194
Gastric acid secretion has been proposed to be regulated by opioid receptors in the central nervous system (CNS). However, whether the effect of morphine is stimulatory or inhibitory, and the role of type specificity of opioid receptors have not been established. We investigated the effects of centrally injected opioid receptor agonists on gastric acid secretion in the perfused stomach of urethane-anesthetized rats. Injection of morphine (1-30 microg/rat, mu-opioid receptor agonist) into the fourth cerebroventricle inhibited the secretion stimulated by i.v. injection of 2-deoxy-D-glucose. Morphine itself did not show an inhibitory effect. In contrast, injection of kappa(1)-opioid receptor agonists such as (5alpha,7alpha,8beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)benzeneacetamide (U59593, 0.3-3 microg) and (trans)-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl) benzeneacetamide hydrochloride (U50488H, 10 microg) and the kappa(2)-opioid receptor agonist, bremazocine (3 microg), into the lateral cerebroventricle markedly stimulated secretion. The effect of U59593 was inhibited by naloxone and norbinaltorphimine (an antagonist of kappa-opioid receptors) and in vagotomized rats. [D-Pen(2)-D-Pen(5)]enkephalin (10microg, delta-opioid receptor agonist) had no effect on secretion. The dual roles of the opioid system in the CNS in gastric acid secretion are discussed. 相似文献
16.
Loperamide (0.1-3.2mg/kg i.p.) produced dose-dependent and complete suppression of writhing in the acetic acid-induced writhing assay in mice. Naltrexone (NTX; 0.1-10.0mg/kg s.c.) and its N-methylated derivative quaternary naltrexone (QNTX; 1.0 and 10.0mg/kg s.c.) were roughly equipotent in antagonizing the antinociceptive effects of loperamide. In contrast, NTX was approximately 100-fold more potent than QNTX in antagonizing the antinociceptive effects of the classical mu agonist morphine. Furthermore, the antinociceptive effects of loperamide were not antagonized by central administration of the selective mu antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP; 300ng i.c.v.), or by systemic administration of either the kappa selective antagonist nor-binaltorphimine (nor-BNI; 32.0mg/kg s.c.), or the delta antagonist naltrindole (NTI; 10.0mg/kg s.c.). These doses of CTAP, nor-BNI and NTI were effective antagonists of morphine, the kappa agonist U69,593 and the delta agonist BW 373U86 [(+/-)-4-((R*)-a-((2S*5R*)-4-allyl-2,5-dimethyl-1- piperazinal)-3-hydroxybenzyl)-N, N-diethylbenzamide dihydrochloride], respectively. These results indicate that the antinociceptive effects of loperamide in mice are mediated, at least in part, by opioid receptors; however, these receptors are distinct from the opioid receptors mediating the effects of morphine, U69,593 and BW 373U86. These results are consistent with the hypothesis that loperamide produces its antinociceptive effects by acting, at least in part, at peripheral opioid receptors. 相似文献
17.
1. Ethylketocyclazocine (EKC) and U50,488H have been employed widely as kappa-receptor agonists in the study of opioid receptor systems. However, the quantification of their agonism in terms of affinities and relative efficacies has not been investigated. 2. In this study, operational model-fitting was used to analyse the effects of irreversible receptor alkylation by beta-chlornaltrexamine (beta-CNA) on the kappa-receptor mediated effects of EKC and U50,488H in the isolated, coaxially stimulated ileum of the guinea-pig. 3. EKC produced monophasic inhibitory concentration-effect curves which were readily amenable to analysis. In contrast U50,488H produced biphasic curves characterized by a higher potency phase of agonism that was susceptible to antagonism by 16-methylcyprenorphine (RX8008M) and a lower potency phase that was apparently non-opioid in nature. 4. Analysis of the kappa-receptor-mediated effects of both agonists indicated that EKC has fifteen fold higher affinity than U50,488H and that the two agonists possess similar intrinsic efficacies. 相似文献
18.
In the present study, the effect of histamine agonists and antagonists on morphine antinociception and naloxone antagonism were studied. The antinociceptive effect of morphine and the antagonistic effect of naloxone were measured by the acetic acid-induced abdominal constriction test in mice. It was found that pretreatment with 2-methylhistamine, a histamine H1-receptor agonist, altered neither the antinociceptive effect of morphine nor the antagonistic effect of naloxone. When 2-methylhistamine was given together with morphine as pretreatment, the naloxone potency was enhanced compared with pretreatment by morphine alone. Pretreatment with 2-pyridylethylamine, another histamine H1-receptor agonist, alone or in combination with morphine, altered neither the antinociceptive activity of morphine nor the antagonistic potency of naloxone. Pretreatment with 4-methylhistamine, a histamine H2-receptor agonist, did not alter the antinociceptive activity of morphine or the antagonistic effect of naloxone. However, when given together with morphine as the pretreatment, the antinociceptive effect of morphine as well as the antagonistic activity of naloxone were enhanced. Similar effects were observed with dimaprit, another histamine H2-receptor agonist. Pretreatment with diphenhydramine, a histamine H1-receptor antagonist, alone or in combination with morphine, altered neither the antinociceptive effect of morphine nor the antagonistic activity of naloxone. Pretreatment with cimetidine, a histamine H2-receptor antagonist, did not affect the antinociceptive effect of morphine and the antagonistic potency of naloxone. However, when given together with morphine as pretreatment, it suppressed the ability of morphine in inducing an increase in naloxone potency. Similar effects were observed with ranitidine, another histamine H2-receptor blocker.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
19.
This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of μ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (μ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule. After training, correct-key responding averaged 94.4 (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50488. Combining high doses of morphine with low doses of U50488 produced responding on the morphine key and combining high doses of U50488 with low doses of morphine produced responding on the U50488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50488 key. The four-choice procedure under the FR schedule has the potential for determining the discriminative stimulus effects of mixed agonists. 相似文献
20.
Evidence that the kappa agonist U50488H has non-opioid actions 总被引:1,自引:0,他引:1
The antagonism of the antinociceptive effects of various kappa-opioid agonists has been studied in the mouse abdominal constriction test. Naloxone produced a much smaller degree of antagonism of U50488H than it did of two other kappa-agonists, U69593 and tifluadom. The kappa-selective antagonist, norbinaltorphimine, also failed to shift the dose-response curve to U50488H in this test, despite producing considerable antagonism of the U50488H effect in the rotarod test and of U69593 in both experimental situations. These results are suggestive of a non-opioid component to the action of U50488H in the abdominal constriction test. At high concentrations, U50488H, but not U69593, also showed non-opioid effects in reducing contractile activity in the field-stimulated isolated guinea-pig ileum, as demonstrated by the profile of antagonism seen with beta-chlornaltrexamine and naloxone. These results suggest that U69593, rather than U50488H, may be the kappa-agonist of choice to use, particularly in in-vivo experiments. 相似文献