Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:025300 (mu opioid receptor)
 1,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dose-effect curves were determined for phenazocine (0.64-2.5 mg/kg), ketazocine (1.25-80 mg/kg) and ethylketazocine (1.25-80 mg/kg) in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. All three opioid agonists decreased responding with the larger doses. The effects of phenazocine were completely antagonized by small doses of naloxone (0.01-1 mg/kg), whereas the effects of ethylketazocine required larger doses of naloxone (1-10 mg/kg) to be completely antagonized. The behavioral effects of ketazocine were partially attenuated by naloxone, but were not antagonized completely even by a 10 mg/kg dose of naloxone. These data from the pigeon are consistent with previous interpretations that the effects of phenazocine are mediated by actions at a mu opioid receptor, whereas the effects of ketazocine and ethylketazocine are mediated by actions at a kappa opioid receptor.
Neuropharmacology 1982 Sep
PMID:Effects of ketazocine, ethylketazocine and phenazocine on schedule-controlled behavior: antagonism by naloxone. 612 93

Although it is well established that the analgesic effects of morphine are mediated by opioid receptors, previous studies have shown that some opioids additionally inhibit the uptake of serotonin and norepinephrine. The present investigation of a diverse group of opioids revealed that structurally identifiable subgroups inhibited the neuronal reuptake of these monoamines. Phenanthrene opioids with an oxygen bridge between C4 and C5, such as morphine and naloxone (group I), did not block norepinephrine or serotonin uptake, whereas phenanthrene opioids without the oxygen bridge and the C6-OH moiety, such as levorphanol and levomethorphan (group II), did inhibit uptake, as did nonphenanthrene opioids, such as d-propoxyphene and methadone (group III). Affinity at the mu opioid receptor correlated with antinociceptive potency (r = 0.87, P < .05). Although the antinociceptive activity of the "active enantiomers" of group II and III compounds also correlated with their affinity at the mu opioid receptor (r = 0.85, P = .007), additional consideration of serotonin uptake inhibiting activity (but not of norepinephrine uptake inhibiting activity) significantly improved the correlation between antinociceptive potency and the in vitro activity of these compounds (r = 0.915, P = .0017). Additionally, for group II and III (but not group I) compounds, smaller differences between enantiomers in antinociceptive potency than in mu receptor affinity were noted, presumably because of the contribution of uptake inhibition to the antinociceptive activity of group II and III compounds. Evidence also is provided suggesting a broader role for the combination of mu opioid affinity and 5-hydroxytryptamine uptake inhibition in the activity of other antinociceptive agents.
J Pharmacol Exp Ther 1995 Sep
PMID:Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. 756 97

Endogenous purinergic systems are important in spinal mechanisms of antinociception. Antinociception induced by spinal mu opioid receptor-selective agonists, in particular, appears to be mediated in part by opioid-stimulated adenosine release. Nucleoside transport system(s) have been implicated both in adenosine release and in its reuptake at spinal sites. The present investigations were designed to determine the significance of nucleoside transport system(s) inhibition in vivo in antinociception induced by opioids administered intrathecally in mice. Dilazep, but not dipyridamole or s (4-nitrobenzyl)-6-thioinosine, nucleoside transport system(s) inhibitors, induced time- and dose-dependent antinociception in the tail-flick test, putatively via spinal adenosine reuptake inhibition. Each nucleoside transport system(s) inhibitor, at doses that have no significant effects alone, enhanced adenosine-mediated antinociception when coadministered intrathecally. Concurrent treatment of mice with opioid receptor-selective agonists and nucleoside transport system(s) inhibitors had varying effects on antinociception, depending on the timing of the nucleoside transport inhibitor. In general, antinociception induced by mu opioid receptor-selective agonists was inhibited by pretreatment, was not affected after coadministration and was enhanced by post-treatment, with nucleoside transport system(s) inhibitors. In contrast, antinociception induced by delta opioid receptor-selective agonists was enhanced by nucleoside transport system(s) inhibitors in all treatment protocols. These results provide in vivo evidence that alterations in adenosine movements into or out of spinal neurons via the nucleoside transport systems can induce antinociception and enhance or inhibit opioid-mediated antinociception. These data also support the hypothesis that adenosine plays significant but independent roles in antinociception induced by mu and delta opioid receptor-selective agonists.
J Pharmacol Exp Ther 1995 Sep
PMID:Time-dependent antinociceptive interactions between opioids and nucleoside transport inhibitors. 756 12

The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the sigma 1 receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The (-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (< 0.05 microM), and all except the (-)-methyl homolog interacted reasonably well at the delta receptor (K(i) < 0.1 microM). The (-)-propyl compound was equipotent (K(i) 1.5-2.0 nM) at mu and kappa receptors. The pattern of interaction of the (-)-enantiomeric homologs with mu receptors from rat and monkey preparations was similar, but not identical. The enantioselectivity of the homologs for mu receptors was greater in the rat than in the monkey preparation for all but the N-H and butyl compounds, and the enantioselectivity of the lower homologs (methyl through butyl) for the mu (monkey) receptor was greater than for the kappa or delta receptors. However, bulkier homologs (hexyl through decyl) displayed higher enantioselectivity at kappa or delta receptors than at the mu (monkey) receptor. The (+)-butyl through (+)-octyl homologs were essentially equipotent with, or more potent than, (+)-pentazocine at the sigma receptor. Only the (+)-H and (+)-methyl homologs had high affinity (< 0.05 microM) at PCP binding sites.
J Med Chem 1994 Sep 30
PMID:Antipodal alpha-N-(methyl through decyl)-N-normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans): in vitro and in vivo properties. 793 69

We have isolated mouse mu opioid receptor genomic clones (termed MOR) containing the entire amino acid coding sequence corresponding to rat MOR-1 cDNA, including additional 5' flanking sequence. The mouse MOR gene is > 53 kb long, and the coding sequence is divided by three introns, with exon junctions in codons 95 and 213 and between codons 386 and 387. The first intron is > 26 kb, the second is 0.8 kb, and the third is > 12 kb. Multiple transcription initiation sites were observed, with four major sites confirmed by 5' rapid amplification of cDNA ends and RNase protection located between 291 and 268 bp upstream of the translation start codon. Comparison of the 5' flanking sequence with a transcription factor database revealed putative cis-acting regulatory elements for transcription factors affected by cAMP, as well as those involved in the action of gluco- and mineralocorticoids, cytokines, and immune-cell-specific factors.
Proc Natl Acad Sci U S A 1994 Sep 13
PMID:Genomic structure analysis of promoter sequence of a mouse mu opioid receptor gene. 809 Jul 73

Previous reports show the tail-flick inhibition induced by bremazocine given i.c.v. is mediated by supraspinal stimulation of both epsilon and kappa opioid receptors and the spinal activation of descending serotonergic and opioid systems. The present studies questioned what endogenous opioid peptides in the spinal cord were involved in i.c.v. bremazocine-induced antinociception in male ICR mice. beta-Endorphin, trans(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzene-acetamide methane sulfonate (U50,488H) and morphine were used as reference compounds for epsilon, kappa and mu opioid receptor activity, respectively. Intrathecal pretreatment with antibody to Met-enkephalin dose-dependently attenuated the antinociception induced by i.c.v. bremazocine or beta-endorphin but not morphine or U50,488H; whereas intrathecal (i.t.) pretreatment with antibody to dynorphin A (1-13) dose-dependently blocked the antinociception induced by i.c.v. bremazocine or U50,488H but not beta-endorphin or morphine. Intrathecal Leu-enkephalin and beta-endorphin antibodies did not block i.c.v. bremazocine, beta-endorphin or morphine antinociception. Intrathecal Met-enkephalin or dynorphin A (1-17) increased the tail-flick latency at 1 to 2 min. Met-enkephalin given i.t. blocked the antinociception induced by i.c.v. DPDPE, bremazocine and beta-endorphin but not morphine or U50,488H whereas i.t. dynorphin A (1-17) pretreatment blocked the inhibition induced by i.c.v. U50,488H and bremazocine but not DPDPE, beta-endorphin or morphine. Bremazocine given i.c.v. did not exhibit antianalgesic activity in our studies. The dynorphin released by i.c.v. bremazocine for antinociception appears to be different from the dynorphin released by morphine for antianalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
J Pharmacol Exp Ther 1993 Sep
PMID:Spinal involvement of both dynorphin A and Met-enkephalin in the antinociception induced by intracerebroventricularly administered bremazocine but not morphine in the mouse. 810 94

1. The evidence for kappa-receptor heterogeneity is equivocal. We have now investigated this question by comparing the effects of five putatively selective kappa-agonists. The parameters examined were: the relative potencies in depressing hindlimb flexor muscle reflexes to noxious pinch stimuli in both spinalized and sham-spinalized rats; the reversibility of these effects by naloxone; and the effects on blood pressure. 2. Two types of drug effect was discriminated. One drug group, represented by U-50,488, U-69,593 and PD-117,302, had a potency ratio between sham and spinalized rats approximately 10 fold lower than the other group, which comprised GR103545 and CI-977. 3. Under sham-spinalized conditions, CI-977 and GR103545 at high doses caused only sub-maximal reductions of spinal reflexes. U-50,488 was still active when superimposed on these high doses of GR103545. 4. Naloxone reversed all effects, but different doses were required between compounds, with GR103545 taking some 20 times higher doses of naloxone to cause reversal than did U-50,488. 5. The effects on mean arterial pressure were opposite between groups. 6. The results imply that more than one type of naloxone-sensitive non-mu opioid receptor must be involved in mediating these complex actions of ligands that have been claimed to be selective for kappa-receptors.
Br J Pharmacol 1993 Sep
PMID:Functional evidence for multiple receptor activation by kappa-ligands in the inhibition of spinal nociceptive reflexes in the rat. 822 Aug 93

In unmodified synaptosomal brain membranes the presence of NaCl inhibited the binding to mu receptors of the tritiated opioid agonists etorphine, Tyr-D-Ala-Gly-(Me)Phe-Gly-ol, and sufentanil by 53, 43, and 37%, respectively, and increased that of the antagonist [3H]naltrexone by 54%. On the other hand, in membranes whose microviscosity was increased by incorporation of cholesteryl hemisuccinate (CHS) the effects of sodium on opioid agonist and antagonist binding were abolished and strongly reduced, respectively. Furthermore, in the modified membranes the ability of sodium to protect the opioid receptor from inactivation by the sulfhydryl-reactive agent N-ethylmaleimide (NEM) was diminished. In CHS-treated membranes whose elevated microviscosity was reduced by the incorporation of oleic acid, the effectiveness of sodium in modulating opioid binding and attenuating receptor inactivation by NEM was restored. The results implicate membrane microviscosity in the mechanism by which sodium modulates the conversion between agonist- and antagonist-favoring states of mu opioid receptor.
J Neurochem 1993 Sep
PMID:Altered transition between agonist- and antagonist-favoring states of mu-opioid receptor in brain membranes with modified microviscosity. 839 59

The sequence of the mu opioid receptor is highly conserved among human, rat, and mouse. In order to gain insights into the evolution of the mu opioid receptor, polymerase chain reaction (PCR) was used to screen genomic DNA from a number of different species using degenerate oligonucleotides which recognize a highly conserved region. DNA was assayed from representative species of both the protostome and deuterostome branches of the metazoan phylogenetic tree. Mu opioid receptor-like sequences were found in all vertebrate species that were analyzed. These species included bovine, chicken, bullfrog, striped bass, thresher shark, and Pacific hagfish. However, no mu opioid receptor-like sequences were detected from protostomes or from any invertebrates. The PCR results demonstrate that the region of the mu opioid receptor gene between the first intracellular loop and the third transmembrane domain (TM3) has been highly conserved during evolution and that mu opioid receptor-like sequences are present in the earliest stages of vertebrate evolution. Additional opioid receptor-like sequence was obtained from mRNA isolated from Pacific hagfish brain using rapid amplification of cDNA ends (RACE). The sequence of the Pacific hagfish was most homologous with the human mu opioid receptor (72% at the amino acid level between intracellular loop 1 and transmembrane domain 6) although over the same region high homology was also observed with the delta opioid receptor (69%), the kappa receptor (63%), and opioid receptor-like (ORL1) (59%). The hagfish sequence showed low conservation with the mammalian opioid receptors in the first and second extracellular loops but high conservation in the transmembrane and intracellular domains.
J Mol Evol 1996 Sep
PMID:Mu opioid receptor-like sequences are present throughout vertebrate evolution. 870 83

In C6 glioma cells stably expressing a homogeneous population of the cloned rat mu opioid receptor, the binding affinities of opioid agonists and subsequent activation of G protein were examined. Opioid receptor number in membranes of these cells was high (10-30 pmol/mg protein [3H]diprenorphine binding sites). Opioids were found to bind to the receptor with high affinity [Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAMGO) 0.23 nM; sufentanil 0.034 nM; morphine 0.16 nM]. Activation of G protein by opioid agonists was examined by measuring the stimulation of guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding. Sufentanil increased [35S]GTP gamma S binding by 326% with an EC50 value of 2.39 nM. Agonist stimulation of [35S]GTP gamma S binding was stereoselective, naltrexone-reversible, and pertussis toxin-sensitive. The "intrinsic activity" of opioids at the mu receptor was reflected by the magnitude of agonist-mediated activation of G protein. The rank order of the stimulation of [35S]GTP gamma S binding was etonitazene = sufentanil = DAMGO = PLO17 = fentanyl > morphine > profadol > meperidine > butorphanol = nalbuphine = pentazocine > cyclazocine = nalorphine > levallorphan > naltrexone. High affinity binding of ligands to the mu opioid receptor was reduced by the addition of sodium and guanosine diphosphate at concentrations used in the [35S]GTP gamma S binding assay. Ligand affinity was reduced in a manner correlating with "intrinsic activity". DAMGO, 1229-fold, nalbuphine 35-fold, naltrexone, 3-fold. The results presented show that the stable expression of the rat mu opioid receptor in C6 cells provides an effective tool to examine opioid receptor signal transduction mechanisms and evaluate the activity of novel opioids at the mu receptor.
J Pharmacol Exp Ther 1996 Sep
PMID:Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor. 881 94


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