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)

The purpose of the present study was to characterize opioid receptor-mediated regulation of incertohypothalamic dopaminergic (DA) neurons in the rat brain by examining the acute effects of selective mu or kappa opioid receptor agonists and antagonists on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial zona incerta (MZI) and the dorsomedial hypothalamic nucleus (DMN) which contain cell bodies and terminals, respectively, of these neurons. Morphine caused a dose- and time-related increase in concentrations of DOPAC in MZI and DMN; this stimulatory effect was blocked by the mu opioid receptor antagonist naltrexone. In contrast, activation or blockade of kappa opioid receptors following administration of U-50,488 or nor-binaltorphimine, respectively, had no effect on DOPAC concentrations in either the MZI or DMN. The basal activity of incertohypothalamic DA neurons and their response to morphine was similar in male and female rats. Morphine also increased the concentrations of 5-hydroxyindoleacetic acid in MZI and DMN, indicating that morphine increases the activity of 5-hydroxytryptamine (5HT) neurons projecting to these regions. This might suggest that morphine-induced activation of incertohypothalamic DA neurons is mediated by 5HT neurons; but 5,7-dihydroxytryptamine-induced lesions of 5HT neurons did not alter the ability of morphine to increase DOPAC concentrations in MZI and DMN. These results indicate that the stimulatory effects of mu opioid receptor activation on incertohypothalamic DA neurons is not dependent upon the presence of 5HT neurons.
Brain Res 1992 Sep 18
PMID:Characterization of opioid receptor-mediated regulation of incertohypothalamic dopamine neurons: lack of evidence for a role of 5-hydroxytryptaminergic neurons in mediating the stimulatory effects of morphine. 133 99

We have recently demonstrated that [3H]ohmefentanyl, a non-peptidergic opioid ligand which was suggested to cross the blood brain barrier in contrast to other peptidergic opioid ligands, bound not only to mu opioid receptor sites but also to sigma sites. In order to examine whether [3H]ohmefentanyl can be used as a marker for mu sites, we investigated the effects of brain lesions on [3H]ohmefentanyl binding site densities, as compared with [3H][D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]DAGO), a selective mu ligand. These binding site densities were measured by quantitative autoradiography in the rat striatum and substantia nigra, two brain structures known to contain a high density of mu receptors, following lesions of the nigro-striatal dopaminergic pathway and striatal intrinsic neurons. Following unilateral nigral lesion with 6-hydroxydopamine, [3H]ohmefentanyl binding site densities were decreased in the patches (-35%) and matrix (-20%) of the ipsilateral striatum and in the lesioned substantia nigra pars compacta (-49%). Unilateral striatal lesion with quinolinic acid induced 72%, 61% and 50% decreases in [3H]ohmefentanyl binding in the patches and matrix of the lesioned striatum and in the ipsilateral substantia nigra pars reticulata, respectively. Similar results were obtained in the binding of [3H]DAGO. Indeed, a significant linear correlation was observed between [3H]ohmefentanyl and [3H]DAGO binding site densities. Therefore, mu opioid receptors may be mainly located on intrinsic neurons in the striatum, dopaminergic cell bodies in the substantia nigra pars compacta and nerve terminals of striatal efferents in the substantia nigra pars reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)
Chem Pharm Bull (Tokyo) 1992 Sep
PMID:Effect of brain lesions on [3H]ohmefentanyl binding site densities in the rat striatum and substantia nigra. 133 31

Equipotent antinociceptive doses, as determined by a tail-flick response, for centrally administered (periaqueductal gray) morphine (M) and D-Ala2, D-Leu5 enkephalin (DADLE) were established as 5 micrograms and 19 micrograms, respectively. Chronic (28 day) subcutaneous infusion of clomipramine (CMI) via an Alzet minipump attenuated both central M-and DADLE-induced analgesia by day 15; attenuation persisted for the duration of the infusion (day 29). Within 7 days following removal of the pump, antinociceptive responses to M and DADLE returned to near pre-CMI levels. Our results indicate a similarity between M and DADLE with regard to attenuation of their antinociceptive action by chronic CMI. This attenuation may be due to decreased mu opioid receptor sensitivity or density resulting from chronic tricyclic antidepressant administration.
Pain 1990 Sep
PMID:Effects of chronic clomipramine on central DADLE antinociception. 225 Sep 23

[3H]beta-funaltrexamine ([3H]beta-FNA) bound irreversibly to bovine striatal membranes. Naloxone inhibited the irreversible binding of 5 nM [3H]beta-FNA in a dose-dependent manner and maximally inhibited this binding at approximately 1 microM. Thus, the specific irreversible binding of [3H]beta-FNA to opioid receptors was defined as that which could be inhibited by 1 microM naloxone. This specific irreversible binding of [3H]beta-FNA was characterized. Exclusion of Na+ from the incubation medium reduced the specific binding of [3H]beta-FNA, and Na+ could be substituted by Li+ but not by K+, Cs+, Mg2+, or guanylylimidodiphosphate. The specific irreversible binding was saturable, time- and temperature-dependent, and was linearly related to tissue mass. Several drugs were used to characterize this specific binding. Levorphanol was 1000 times more potent as an inhibitor than dextrorphan. mu Opioid ligands (sufentanil and morphine) were much better inhibitors than delta (ICI174,864) or kappa (U50,488H) ligands. The potency of [D-Ala2, D-Leu5]enkephalin (DADLE) was between those of sufentanil and ICI174,864. These results demonstrated that under appropriate conditions [3H]beta-FNA specifically and irreversibly bound to the mu opioid binding site. Membrane preparations labeled with [3H]beta-FNA in the presence or absence of 1 microM naloxone or beta-FNA were subjected to polyacrylamide gel electrophoresis under denaturing and reducing conditions. Fluorograms showed that [3H]beta-FNA specifically bound to a protein (most likely the mu opioid binding site) that migrated as a band with a molecular weight range of 68,000-97,000. Such electrophoretic behavior indicates that it is likely to be a glycoprotein. The glycoprotein nature was confirmed by its adsorption onto a wheat germ lectin-Sepharose column after solubilization and subsequent elution by N-acetyl-D-glucosamine. In this lectin column eluate, the mu opioid receptor was the only protein band labeled by [3H]beta-FNA in the total binding preparation, and no labeled protein was observed in the nonspecific binding preparation. When the wheat germ lectin column eluate of the total binding was treated with peptide:N-glycosidase F, the broad labeled band of Mr 68,000-97,000 became a sharp band of Mr 57,000 with high radioactivity and a faintly labeled band of Mr 49,000.
Mol Pharmacol 1987 Sep
PMID:Covalent labeling of mu opioid binding site by [3H]beta-funaltrexamine. 282 89

Reconstitution of purified mu opioid receptors with purified guanine nucleotide-binding regulatory proteins (G proteins) was investigated. mu opioid receptors were purified by 6-succinylmorphine AF-AminoTOYOPEARL 650M affinity chromatography and by PBE isoelectric chromatography. The purified mu opioid receptor (pI 5.6) migrated as a single Mr 58,000 polypeptide by NaDodSO4/PAGE, a value identical to that obtained by affinity cross-linking purified mu receptors. When purified mu receptors were reconstituted with purified Gi, the G protein that mediates the inhibition of adenylate cyclase, the displacement of [3H]naloxone (a mu opioid antagonist) binding by [D-Ala2,MePhe4,Gly-ol5]enkephalin (a mu opioid agonist) was increased 215-fold; this increase was abolished by adding 100 microM (guanosine 5'-[gamma-thio]triphosphate. Similar increases in agonist displacement of [3H]naloxone binding (33-fold) and its abolition by guanosine 5'-[gamma-thio]triphosphate were observed with Go, the G protein of unknown function, but not with the v-Ki-ras protein p21. In reconstituted preparations with Gi or Go, neither [D-Pen2,D-Pen5]enkephalin (a delta opioid agonist; where Pen is penicillamine) nor U-69,593 (a kappa opioid agonist) showed displacement of the [3H]naloxone binding. In addition, the mu agonist stimulated both [3H]guanosine 5'-[beta,gamma-imido]triphosphate binding (in exchange for GDP) and the low-Km GTPase in such reconstituted preparations, with Gi and Go but not with the v-Ki-ras protein p21, in a naloxone-reversible manner. The stoichiometry was such that the stimulation of 1 mol of mu receptor led to the binding of [3H]guanosine 5'-[beta,gamma-imido]triphosphate to 2.5 mol of Gi or to 1.37 mol of Go. These results suggest that the purified mu opioid receptor is functionally coupled to Gi and Go in the reconstituted phospholipid vesicles.
Proc Natl Acad Sci U S A 1988 Sep
PMID:Reconstitution of rat brain mu opioid receptors with purified guanine nucleotide-binding regulatory proteins, Gi and Go. 284 1

The activity of ketocyclazocine, a putative kappa opioid receptor agonist, was studied and compared with that of morphine, a mu opioid receptor agonist, and cyclazocine, a putative kappa and sigma opioid receptor agonist, vs. placebo in 10 drug abusers. The measures included vital signs and pupil measurements, established and new observer- and subject-completed psychopharmacologic questionnaires and several methods of drug discrimination. The results indicate that ketocyclazocine is different from morphine-like agonists in that it produces only minimal miosis and lacks euphoriant action. It causes a dysphoric state and was clearly discriminated from morphine. The dysphoria and pattern of responses was similar to cyclazocine though ketocyclazocine was discriminated from cyclazocine. This is consistent with the concept that morphine and ketocyclazocine have separate modes of primary activity. The similarity between ketocyclazocine and cyclazocine obscures the assignment of particular drug effects to activity at the kappa receptor.
J Pharmacol Exp Ther 1986 Sep
PMID:Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo. 301 28

Thought process common to many medicinal chemists are exposed in this example dealing with the quest for the discovery of new analgesic agents. The unexpected course of a chemical reaction, and subsequent random screening of the product, led to the serendipidous finding of CNS activity in the phenylcyclohexylamine derivative (9). In the development of the lead, synthetic targets were continually adjusted as the result of subsequent biological testing, and finally produced two compounds (34 and 35) with clinical potential as analgetics. Each failed to enter clinical testing due to their toxicity, but the overall results led to new concepts of the nature of the mu opioid receptor.
Drug Des Deliv 1987 Sep
PMID:Exploration of a chemical series as a drug discovery strategy. 333 46

Metorphamide is a [Met]-enkephalin-containing opioid octapeptide with a C-terminal alpha-amide group. It is derived from proenkephalin and is, so far, the only endogenous opioid peptide with a particularly high affinity for mu opioid (morphine) receptors, a somewhat lesser affinity for kappa opioid receptors, and a relatively low affinity for delta opioid receptors. The concentrations of metorphamide in the bovine caudate nucleus, the hypothalamus, the spinal cord, and the neurointermediate pituitary were determined by radioimmunoassay and chromatography separation procedures. Metorphamide concentrations were compared with the concentrations of eight other opioid peptides from proenkephalin and prodynorphin in identical extracts. The other opioid peptides were [Met]-enkephalyl-Arg6-Phe7 and [Met]-enkephalyl-Arg6-Gly7-Leu8 from proenkephalin; alpha-neoendorphin, beta-neoendorphin, dynorphin A(1-8), dynorphin A(1-17), and dynorphin B from prodynorphin; and [Leu]-enkephalin, which can be derived from either precursor. All opioid peptides were present in all four bovine neural tissues investigated. Metorphamide concentrations were lower than the concentrations of the other proenkephalin-derived opioid peptides. They were, however, similar to the concentrations of the prodynorphin-derived opioid peptides in the same tissues. Marked differences in the relative ratios of the opioids derived from prodynorphin across brain regions were observed, a finding suggesting differential posttranslational processing. Differences in the ratios of the proenkephalin-derived opioids across brain regions were less pronounced. The results from this study together with previous findings on metorphamide's mu opioid receptor binding and bioactivities suggest that the amounts of metorphamide in the bovine brain are sufficient to make this peptide a candidate for a physiologically significant endogenous mu opioid receptor ligand.
J Neurochem 1987 Sep
PMID:Distribution pattern of metorphamide compared with other opioid peptides from proenkephalin and prodynorphin in the bovine brain. 361 17

Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.
Pain 1987 Sep
PMID:Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. 367 Aug 80

The preferential conformations of the delta selective opioid peptides DPLPE (Tyr-c[D X Pen-Gly-Phe-Pen]) and DTLET (Tyr-D X Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO-d6 solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen5 or Thr6), associated with interproton NH-NH and alpha-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various gamma and/or beta turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable gamma turn around the amino acid in position 2. Finally, a short distance, about 10 A, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for the constrained peptide DPLPE and the flexible hexapeptide DTLET. Therefore, it may be hypothesized that the enhanced delta selectivity of DPLPE is related to a very large conformational expense of energy needed to interact with the mu opioid receptor, a feature not encountered in the case of DTLET. These findings might allow peptides to be designed retaining a high affinity for delta opioid receptors associated with a very low cross-reactivity with mu binding sites.
Int J Pept Protein Res 1987 Sep
PMID:Comparison of conformational properties of linear and cyclic delta selective opioid ligands DTLET (Tyr-D X Thr-Gly-Phe-Leu-Thr) and DPLPE (Tyr-c[D X Pen-Gly-Phe-Pen]) by 1H n.m.r. spectroscopy. 369 82


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