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A Baamonde V Daugé G Gacel B P Roques 《The Journal of pharmacology and experimental therapeutics》1991,257(2):767-773
The mu opioid receptors are unquestionably implicated both in supraspinal and spinal analgesia, but there is some controversy about the role of delta receptors in the control of pain at the supraspinal level. This could be due, at least in part, to the local or i.c.v. administration of the opioid agonists. It was therefore interesting to reassess the overall contribution of mu and delta opioid receptors in modulating nociceptive thermal stimuli in the hot plate-test in mice after i.v. injections of DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) and BUBU (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), two highly selective mu and delta receptor agonists, respectively, whose passage into the brain has been demonstrated recently. Both agonists induced dose-dependent, short-lasting (less than 30 min), antinociceptive responses that peaked 5 min after the administration of DAMGO and 10 min after the administration of BUBU. At these times, DAMGO [ED50: 1.26 mumols (0.65 mg)/kg] was 34 times more potent than BUBU [ED50: 42.5 mumols (34 mg)/kg] in the jump response and 13 times more potent in the paw lick. Apparent pA2 values of naloxone (0.004-0.1 mg/kg s.c.) antagonism for DAMGO and BUBU did not differ significantly, 6.95 +/- 0.054 and 7.28 +/- 0.030 for paw lick tests and 7.11 +/- 0.045 and 7.25 +/- 0.027 for jump tests, respectively. The slopes of the pA2 plots were close to the theoretical -1 value for competitive antagonism.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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J M Soleilhac E Lucas A Beaumont S Turcaud J B Michel D Ficheux M C Fournié-Zaluski B P Roques 《Molecular pharmacology》1992,41(4):609-614
Neutral endopeptidase 24.11 (EC 3.4.24.11) inactivates atrial natriuretic peptide by cleaving the hormone between Cys7 and Phe8, and inhibitors of the enzyme have consequent natriuretic and diuretic properties. The in vivo sites of degradation of this peptide by the zinc-metallopeptidase, however, remain to be established. Because an endopeptidase-24.11-like activity has recently been reported in the rat mesenteric artery, we have further investigated the degradation of atrial natriuretic peptide in vascular tissue. Endopeptidase-24.11 activity was detected in solubilized membrane preparations from rat and rabbit vascular tissue, using [3H]D-Ala2-leucine enkephalin as substrate, and both rabbit and rat aorta preparations were also found to cleave atrial natriuretic peptide between Cys7 and Phe8. In both cases, hydrolysis was inhibited by neutral endopeptidase inhibitors, with Ki values close to their Ki values for the pure enzyme. In preparations of rabbit aorta denuded of endothelium by saponin treatment, the hydrolysis of the Gly3-Phe4 bond of [3H]D-Ala2-leucine enkephalin and the Cys7-Phe8 bond of atrial natriuretic peptide was reduced by greater than 90%. The high performance liquid chromatography method used to follow the degradation of atrial natriuretic peptide differed from previously published procedures, in that samples to be injected were first treated with excess dithiothreitol to reduce the Cys7-Cys23 disulfide bridge. This facilitated the separation of the intact peptide and its metabolites. The presence of the 94-kDa neutral endopeptidase in rabbit aortic tissue was definitively established using a new potent 125I-labeled inhibitor, [125I]RB104 [2-[(3-[125I]iodo-4-hydroxy)phenylmethyl]-4-N-[3- hydroxyamino-3-oxo-1-phenylmethyl propyl]amino-4-oxobutanoic acid] (Ki, 30 pM), which selectively labeled the enzyme after sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the membrane preparations. Therefore, despite its low concentrations in the vasculature, the presence of endopeptidase-24.11 almost exclusively in endothelial tissue suggests that the enzyme is ideally localized to inactivate circulating atrial natriuretic peptide. 相似文献
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P E Milhiet A Beaumont C Garbay-Jaureguiberry B P Roques 《Biochemical pharmacology》1992,43(8):1711-1715
Neutral endopeptidase (EC 3.4.24.11, NEP) is an ectoenzyme, identified as the common acute lymphoblastic leukemia antigen (CALLA, CD10). This enzyme is involved in the inactivation of regulatory peptides such as enkephalins and atrial natriuretic peptide and its expression on the cell surface is therefore essential. NEP levels have been measured under different conditions on leukemic cell lines. NEP activity per cell was found to increase during the cell growth of Reh6 and CEM cells, a cell-cell contact mechanism being suggested by experiments using Transwell cell chambers. The same process was not observed with ICIG-7 fibroblasts. The numbers of enzymatic sites was also found to be selectively modulated by treatment with 0.1 microM N-[3-(R,S)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]glycine (HACBOGly), a potent (Ki = 1.4 nM) and specific inhibitor of NEP. A maximal 13% decrease in sites was observed after 8 hr incubation, this effect disappearing after 12 hr. This weak but specific negative modulation was not observed with a compound, chemically related to HACBOGly, which has a 10,000-fold lower inhibitory potency. The modulation was inhibited by low temperature or monensin treatment and could be brought about by an internalization of the enzyme, compensated for by an increased biosynthesis or by the sequestration of NEP in a non-membranous compartment. 相似文献
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Inhibition of morphine withdrawal by the association of RB 101, an inhibitor of enkephalin catabolism, and the CCKB antagonist PD-134,308. 总被引:2,自引:1,他引:1 下载免费PDF全文
R Maldonado O Valverde B Ducos A G Blommaert M C Fournie-Zaluski B P Roques 《British journal of pharmacology》1995,114(5):1031-1039
1. The effects induced in rats on naloxone-precipitated morphine withdrawal syndrome by the new mixed inhibitor of enkephalin catabolism able to cross the blood-brain barrier RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl-L-phenylalanine benzyl ester) given alone or associated with the selective CCKB antagonist, PD-134,308, were investigated. 2. The systemic administration of RB 101 (5, 10 and 20 mg kg-1, i.v.) elicited a significant decrease in 8 of the 14 withdrawal signs evaluated. PD-134,308 (3 mg kg-1, i.p.) did not modify the expression of morphine abstinence when given alone, but induced a strong facilitation of RB 101 responses (12 of 14 withdrawal signs were decreased). This potentiation was particularly intense in peripherally mediated withdrawal signs. 3. In order to clarify the biochemical mechanisms implicated in these responses, the effects induced by the association of RB 101 and PD-134,308 on the occupation of brain opioid receptors by endogenous enkephalins were also investigated in mice. PD-134,308, as well as RB 101, inhibited [3H]-diprenorphine binding to opioid receptors. These results suggest that an increase in endogenous enkephalin levels induced by PD-134,308 could participate in the facilitation of RB 101 behavioural responses. 4. RB 101 has a promising potential role in the management of the opiate withdrawal syndrome. CCKB antagonists, such as PD-134,308 may be useful in potentiating this anti-withdrawal effect. 相似文献
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The CCKB antagonists L-365, 260 and PD134308 and the CCKA antagonist L-364, 718 were applied to neurones of the rat solitary complex (SC) isolated in brainstem slices, while recording either intracellularly or by whole-cell patch-clamp. The CCKB antagonists increased the amplitude of spontaneous or solitary tract-evoked Cl(-)-dependent inhibitory synaptic events by 25 +/- 5% in 5/7 neurones. These events were identified as (1) reversed spontaneous potentials, (2) reversed multisynaptic potentials and (3) outward currents blocked by the GABAA antagonist bicuculline. The CCKB antagonists had no postsynaptic action and increased excitatory synaptic events by 16 +/- 5% in only 3/9 neurones. The CCKA antagonist depolarized neurones but had no effect on synaptic events. Results suggest that CCK, released from the SC tissue, modulates GABAergic interneurones through CCKB sites. This mechanism could contribute to panic attacks, probably mediated by CCKB receptors. 相似文献
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Oscillatory motion of the normal cervical spinal cord 总被引:2,自引:0,他引:2