Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Possible interactions between Met-enkephalin and cholecystokinin (CCK)-containing neurons in the rat substantia nigra were investigated by looking for the effects of various opioid receptor ligands and inhibitors of enkephalin-degrading enzymes on the K(+)-evoked overflow of CCK-like material (CCKLM) from substantia nigra slices. The delta-opioid agonists D-Pen2, D-Pen5-enkephalin (50 microM) and Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET; 3 microM) enhanced, whereas the mu-opioid agonists Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO; 10 microM) and MePhe3, D-Pro4-morphiceptin (PL 017; 10 microM) decreased, the K(+)-evoked release of CCKLM. By contrast, the kappa-opioid agonist U-50488 H (5 microM) was inactive. The stimulatory effect of DTLET could be prevented by the delta antagonist ICI-154129 (50 microM), but not by the mu antagonist naloxone (1 microM). Conversely, the latter drug, but not ICI-154129, prevented the inhibitory effect of DAGO and PL 017. A significant increase in CCKLM overflow was observed upon tissue superfusion with the peptidase inhibitors kelatorphan or bestatin plus thiorphan. This effect probably resulted from the stimulation of delta-opioid receptors by endogenous enkephalins protected from degradation, because it could be prevented by ICI-154129 (50 microM). Furthermore the peptidase inhibitors did not enhance CCKLM release further when delta-opioid receptors were stimulated directly by DTLET (3 microM). These data indicate that opioids acting on delta and mu receptors may exert an opposite influence, i.e., excitatory and inhibitory, respectively, on CCK-containing neurons in the rat substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Opioid control of the in vitro release of cholecystokinin-like material from the rat substantia nigra. 131 Jul 26

Previous studies from our laboratory have indicated that i.c.v. pretreatment of mice with the novel, selective opioid delta receptor antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and naltrindole-5'-isothiocyanate (5'-NTII), differentially antagonized the direct antinociceptive effects of [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II (DELT). These findings, and others, suggested the existence of subtypes of opioid delta receptors which could be classified as activated by DPDPE and DALCE sensitive (delta 1 receptor), or selectively activated by DELT and 5'-NTII sensitive (delta 2 receptor). The present study has extended these observations to the characterization of delta-mediated antinociception effects of DPDPE and DELT after i.t. administration in mice using pretreatment with DALCE and 5'-NTII in order to selectively antagonize the delta subtypes. Additionally, the acute antinociceptive actions of DALCE itself were studied to ensure activity of this compound at the spinal level. The respective antinociceptive A50 value (95% CL) for i.t. DPDPE, DELT and DALCE were 19.0 (12.9-28.1), 19.3 (16.1-23.1) and 2.0 (1.4-3.0) nmol. The delta antagonist, N,N-diallyl-Try-Aib-Aib-Phe-Leu-OH (ICI 174,864) (where Aib is alpha-aminoisobutyric acid) blocked the antinociceptive effects of DPDPE and DELT, but not those of i.t. morphine or [D-Ala2,NMPhe4,Gly-ol5]enkephalin (DAMGO), indicating that the observed antinociceptive effects of DPDPE and DELT were delta mediated. Pretreatment 24 hr before testing with graded doses of i.t. 5'-NTII blocked the i.t. antinociceptive effects of DPDPE and DELT, although at least a 10-fold higher dose of 5'-NTII was needed to produce equivalent antagonism of DPDPE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Spinal opioid delta antinociception in the mouse: mediation by a 5'-NTII-sensitive delta receptor subtype. 131 Jul 37

The inhibition of the tail-flick response induced by beta-endorphin given i.c.v. has been demonstrated to be mediated by the stimulation of epsilon- but not mu-, delta- or kappa-opioid receptors. beta-Endorphin given i.t. also inhibited the tail-flick response. The present studies were designed to determine what types of opioid receptors in the spinal cord were involved in i.t. beta-endorphin-induced tail-flick inhibition. Blockade of kappa-opioid receptors by coadministration of nor-binaltorphimine or Win 44,441-3 with beta-endorphin given i.t. dose dependently inhibited i.t. beta-endorphin-induced inhibition of the tail-flick response. Blockade of mu-opioid receptors by i.t. coadministration of D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 with beta-endorphin blocked i.t. beta-endorphin-induced inhibition of the tail-flick response. I.t. injection of delta-opioid receptors antagonists, ICI 174,864 and naltrindole, or epsilon-opioid receptor antagonist, beta-endorphin-(1-27), did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. Blockade of alpha 2-adrenoceptors and 5-HT receptors by i.t. injection of yohimbine and methysergide, respectively, also did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. The results indicate that the inhibition of the tail-flick response induced by beta-endorphin given i.t. is mediated by the stimulation of kappa- and mu-opioid receptors but not delta- and epsilon-opioid receptors, alpha 2-adrenoceptors or 5-HT receptors.
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PMID:The tail-flick inhibition induced by beta-endorphin administered intrathecally is mediated by activation of kappa- and mu-opioid receptors in the mouse. 131 80

Etorphine, a potent opioid agonist, has been reported to bind to both mu and epsilon opioid receptors. The present studies were designed to determine what types of opioid receptors and neurotransmitters for descending pain control systems were involved in antinociception induced by etorphine in mice. Morphine, a typical mu opioid receptor agonist, and beta-endorphin, an epsilon opioid receptor agonist, were used for comparison. Antinociceptive response induced by etorphine (20 ng) given i.c.v was blocked by i.c.v administration of D-Phe-Cys-Tyr-D-Tyr-Orn-Thr-Pen-Thr-NH2 (CTOP, 25 ng) and beta-endorphin-(1-27) [beta-EP-(1-27)] (6 micrograms), but not ICI 174,864 (ICI, 5 micrograms) or norbinaltorphimine (N-BNI, 5 micrograms). The antinociception induced by i.c.v. etorphine was also antagonized by the i.c.v. pretreatment of beta-funaltrexamine (beta-FNA, 50 ng, 24 hr). Intracerebroventricular administration of beta-EP-(1-27) (3 micrograms) caused a further attenuation of the i.c.v. etorphine-induced antinociception in mice pretreated with beta-FNA. The antinociceptive response induced by morphine (2 micrograms) given i.c.v. was blocked by i.c.v. administration of CTOP (25 ng) or beta-FNA (50 ng), but not beta-EP-(1-27) (6 micrograms), ICI (5 micrograms) or N-BNI (5 micrograms). These results indicate that the antinociception induced by etorphine given i.c.v. is mediated by the stimulation of both mu and epsilon opioid receptors whereas the antinociception induced by morphine given i.c.v. is mediated by the stimulation of mu, but not epsilon opioid receptors at supraspinal sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of supraspinal epsilon and mu opioid receptors in inhibition of the tail-flick response induced by etorphine in the mouse. 132 9

beta-Endorphin and morphine produce an increase in the latency of the tail-flick reflex when administered into the PAG of awake rats. The antinociceptive effect of both opioid agonists was blocked by the sequential local injection of either CTP (D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2), a selective mu opioid receptor antagonist, naltrexone, or beta-endorphin (1-27), a putative epsilon opioid receptor antagonist, with minimal selectivity. When either CTP or naltrexone was used as the antagonist, the dose-inhibition curves generated for beta-endorphin and morphine were not parallel, suggesting the involvement of separate and distinct receptors. Also, synergism occurred when a dose of morphine producing submaximum antinociception was administered simultaneously with either a submaximal or ineffective dose of beta-endorphin. Inhibition of the antinociceptive response to beta-endorphin by mu antagonists and the non-selective antagonism of both beta-endorphin and morphine by beta-endorphin (1-27) suggested that epsilon opioid receptors were not involved. Additionally, a mu/delta opioid receptor complex was not involved, since ICI 174,864 (Allyl2-Tyr-Aib-Aib-Phe-Leu-OH), a selective delta opioid receptor antagonist, did not alter the response to beta-endorphin. Thus, although additional characterization is required, beta-endorphin and morphine appear to act (at least in part) through different opioid receptors, demonstrable using selected mu opioid receptor antagonists.
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PMID:Opioid receptors mediating antinociception from beta-endorphin and morphine in the periaqueductal gray. 133 57

Local cerebral glucose utilization, which is a correlate of neuronal activity, was measured to obtain information on the neuroanatomical sites mediating the different behaviors elicited by i.c.v. administration of the opioid peptide beta-endorphin (beta-END). The selective mu and delta opioid receptor antagonists d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH), respectively, were used to characterize the opioid receptor type involved in the actions of beta-END. beta-END was found to produce profound increases in glucose utilization in limbic regions such as the lateral septal nucleus, the amygdalo-hippocampal transition area, the nucleus accumbens and the hippocampal formation. The ventral hippocampus proved the most sensitive structure, displaying increases in glucose utilization of up to 200%; changes in the dorsal part amounted up to 100%. Only moderate effects were induced by beta-END in motor areas, such as the substantia nigra, pars reticulata and the nucleus ruber. This regional pattern of changes is assumed to underlie the epileptogenic-, motivational-, mood- and possibly memory-modulating actions of beta-END. The effects of beta-END on local cerebral glucose utilization were blocked by pretreatment with the mu antagonist, CTOP, whereas the selective delta opioid antagonist ICI 174,864 was less effective. An involvement of predominantly mu opioid receptors in the central actions of beta-END is, therefore, suggested.
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PMID:Neuroanatomical sites mediating the central actions of beta-endorphin as mapped by changes in glucose utilization: involvement of mu opioid receptors. 135 55

The effects on one-way active avoidance conditioning of pre-training, systemic administration of the selective mu-receptor agonist [D-Ala2,N-Me-Phe4, Gly-ol]enkephalin (DAGO), and the selective mu-receptor antagonist (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), were determined in Swiss-Webster mice. A low dose of DAGO (0.92 micrograms/kg) moderately enhanced avoidance acquisition, whereas a 100 micrograms/kg dose of CTOP more dramatically impaired acquisition. However, the avoidance-enhancing dose of DAGO significantly increased locomotor activity as measured in a separate group of mice in the avoidance chamber, and the avoidance-impairing dose of CTOP significantly decreased activity. Under these same training conditions, earlier studies (Schulteis et al. 1988; Schulteis and Martinez 1990) demonstrated that enkephalins impaired avoidance learning, and selective delta-receptor antagonists such as ICI 174,864 enhanced learning; in contrast to the present study, both of these effects were dissociated from performance effects such as alterations in locomotor activity. Taken together, the results suggested that the effects of enkephalins were mediated by the delta-, but not mu-, class of opioid receptor.
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PMID:Roles of delta and mu opioid receptors in mediating the effects of enkephalins on avoidance conditioning. 136 50

The present study has investigated the direct opioid delta receptor-mediated antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II, as well as that of the less delta-selective [D-Ser2,Leu5,Thr6]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala2,Leu5,Cys6] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala2] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala2]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related antinociception which was partially antagonized by either beta-funaltrexamine (beta-FNA) or by ICI 174,864 (N,N-dialyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET antinociception in beta-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the antinociception produced by DSLET in control or in beta-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the antinociception produced by i.c.v. DSLET in either control or in beta-FNA-pretreated mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes. 164 19

The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrol idinyl) cyclohexyl]benzeneacetamide), on U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)benzeneacetamide]- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2, NMePhe4, Gly-ol]enkephalin- (mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significantly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, beta-funaltrxamine (mu antagonist) and ICI 174,864 [N,N,-diallyl-Tyr-(alpha-aminoisobutyric acid)2-Phe-Leu-OH] (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinociception produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.
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PMID:Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT: evidence of kappa opioid receptor multiplicity in mice. 164 25

In synaptosomal membranes from rat brain cortex, in the presence of 150 mM NaCl, the opioid antagonist [3H]naltrexone bound to two populations of receptor sites with affinities of 0.27 and 4.3 nM, respectively. Guanosine-5'-(3-thiotriphosphate) had little modulating effect and did not alter the biphasic nature of ligand binding. On the other hand, receptor-selective opioids differentially inhibited the two binding components of [3H]naltrexone. As shown by nonlinear least-squares analysis, the mu opioids Tyr-D-Ala-Gly-(Me)Phe-Gly-ol or sufentanil abolished high-affinity [3H]naltrexone binding, whereas the delta-selective ligands [D-Pen2,D-Pen5]enkephalin, ICI 174,864, and oxymorphindole inhibited and eventually eliminated the low-affinity component in a concentration-dependent manner. These results indicate that, in contrast to the guanine nucleotide-sensitive biphasic binding of opioid-alkaloid agonists, the heterogeneity of naltrexone binding in brain membranes reflects ligand interaction with different opioid-receptor types.
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PMID:Resolution of biphasic binding of the opioid antagonist naltrexone in brain membranes. 165 89


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