Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla.Enkephalin, Methionine: One of the endogenous pentapeptides with morphine-like activity. It differs from LEU-ENKEPHALIN by the amino acid METHIONINE in position 5. Its first four amino acid sequence is identical to the tetrapeptide sequence at the N-terminal of BETA-ENDORPHIN.Enkephalin, Leucine: One of the endogenous pentapeptides with morphine-like activity. It differs from MET-ENKEPHALIN in the LEUCINE at position 5. Its first four amino acid sequence is identical to the tetrapeptide sequence at the N-terminal of BETA-ENDORPHIN.Enkephalin, Ala(2)-MePhe(4)-Gly(5)-: An enkephalin analog that selectively binds to the MU OPIOID RECEPTOR. It is used as a model for drug permeability experiments.Enkephalin, Leucine-2-Alanine: A delta-selective opioid (ANALGESICS, OPIOID). It can cause transient depression of mean arterial blood pressure and heart rate.Enkephalin, D-Penicillamine (2,5)-: A disulfide opioid pentapeptide that selectively binds to the DELTA OPIOID RECEPTOR. It possesses antinociceptive activity.Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the PRO-OPIOMELANOCORTIN precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; OPIOID PEPTIDES is used for the broader group.Receptors, Opioid: Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known.Receptors, Opioid, delta: A class of opioid receptors recognized by its pharmacological profile. Delta opioid receptors bind endorphins and enkephalins with approximately equal affinity and have less affinity for dynorphins.Receptors, Opioid, mu: A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors.Dynorphins: A class of opioid peptides including dynorphin A, dynorphin B, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors (RECEPTORS, OPIOID, KAPPA) and have been shown to play a role as central nervous system transmitters.Ethylketocyclazocine: A kappa opioid receptor agonist. The compound has analgesic action and shows positive inotropic effects on the electrically stimulated left atrium. It also affects various types of behavior in mammals such as locomotion, rearing, and grooming.Cyclazocine: An analgesic with mixed narcotic agonist-antagonist properties.Narcotic Antagonists: Agents inhibiting the effect of narcotics on the central nervous system.Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle.Carboxypeptidase H: A ZINC-containing exopeptidase primarily found in SECRETORY VESICLES of endocrine and neuroendocrine cells. It catalyzes the cleavage of C-terminal ARGININE or LYSINE residues from polypeptides and is active in processing precursors of PEPTIDE HORMONES and other bioactive peptides.Benzomorphans: Morphine derivatives of the methanobenzazocine family that act as potent analgesics.Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of NALOXONE. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence.D-Ala(2),MePhe(4),Met(0)-ol-enkephalin: A stable synthetic analog of methionine enkephalin (ENKEPHALIN, METHIONINE). Actions are similar to those of methionine enkephalin. Its effects can be reversed by narcotic antagonists such as naloxone.beta-Endorphin: A 31-amino acid peptide that is the C-terminal fragment of BETA-LIPOTROPIN. It acts on OPIOID RECEPTORS and is an analgesic. Its first four amino acids at the N-terminal are identical to the tetrapeptide sequence of METHIONINE ENKEPHALIN and LEUCINE ENKEPHALIN.Analgesics, Opioid: Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.Receptors, Opioid, kappa: A class of opioid receptors recognized by its pharmacological profile. Kappa opioid receptors bind dynorphins with a higher affinity than endorphins which are themselves preferred to enkephalins.Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the ENKEPHALINS, the DYNORPHINS, and the ENDORPHINS. Each of these families derives from different precursors, proenkephalin, prodynorphin, and PRO-OPIOMELANOCORTIN, respectively. There are also at least three classes of OPIOID RECEPTORS, but the peptide families do not map to the receptors in a simple way.Diprenorphine: A narcotic antagonist similar in action to NALOXONE. It is used to remobilize animals after ETORPHINE neuroleptanalgesia and is considered a specific antagonist to etorphine.Narcotics: Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.Etorphine: A narcotic analgesic morphinan used as a sedative in veterinary practice.Thiorphan: A potent inhibitor of membrane metalloendopeptidase (ENKEPHALINASE). Thiorphan potentiates morphine-induced ANALGESIA and attenuates naloxone-precipitated withdrawal symptoms.Oligopeptides: Peptides composed of between two and twelve amino acids.Analgesics: Compounds capable of relieving pain without the loss of CONSCIOUSNESS.Protein PrecursorsMorphinans: Compounds based on a partially saturated iminoethanophenanthrene, which can be described as ethylimino-bridged benzo-decahydronaphthalenes. They include some of the OPIOIDS found in PAPAVER that are used as ANALGESICS.Tiopronin: Sulfhydryl acylated derivative of GLYCINE.Neprilysin: Enzyme that is a major constituent of kidney brush-border membranes and is also present to a lesser degree in the brain and other tissues. It preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin as well as opioid peptides and other biologically active peptides. The enzyme is inhibited primarily by EDTA, phosphoramidon, and thiorphan and is reactivated by zinc. Neprilysin is identical to common acute lymphoblastic leukemia antigen (CALLA Antigen), an important marker in the diagnosis of human acute lymphocytic leukemia. There is no relationship with CALLA PLANT.Adrenal Medulla: The inner portion of the adrenal gland. Derived from ECTODERM, adrenal medulla consists mainly of CHROMAFFIN CELLS that produces and stores a number of NEUROTRANSMITTERS, mainly adrenaline (EPINEPHRINE) and NOREPINEPHRINE. The activity of the adrenal medulla is regulated by the SYMPATHETIC NERVOUS SYSTEM.PyrrolidinesChromaffin Granules: Organelles in CHROMAFFIN CELLS located in the adrenal glands and various other organs. These granules are the site of the synthesis, storage, metabolism, and secretion of EPINEPHRINE and NOREPINEPHRINE.Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Somatostatin: A 14-amino acid peptide named for its ability to inhibit pituitary GROWTH HORMONE release, also called somatotropin release-inhibiting factor. It is expressed in the central and peripheral nervous systems, the gut, and other organs. SRIF can also inhibit the release of THYROID-STIMULATING HORMONE; PROLACTIN; INSULIN; and GLUCAGON besides acting as a neurotransmitter and neuromodulator. In a number of species including humans, there is an additional form of somatostatin, SRIF-28 with a 14-amino acid extension at the N-terminal.Ileum: The distal and narrowest portion of the SMALL INTESTINE, between the JEJUNUM and the ILEOCECAL VALVE of the LARGE INTESTINE.Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.Dihydromorphine: A semisynthetic analgesic used in the study of narcotic receptors.Vas Deferens: The excretory duct of the testes that carries SPERMATOZOA. It rises from the SCROTUM and joins the SEMINAL VESICLES to form the ejaculatory duct.Guinea Pigs: A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.Rats, Inbred Strains: Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding.Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of PAIN, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses.Injections, Intraventricular: Injections into the cerebral ventricles.Corpus Striatum: Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE.Benzylidene Compounds: Compounds containing the PhCH= radical.Injections, Spinal: Introduction of therapeutic agents into the spinal region using a needle and syringe.Carboxypeptidases: Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Myenteric Plexus: One of two ganglionated neural networks which together form the ENTERIC NERVOUS SYSTEM. The myenteric (Auerbach's) plexus is located between the longitudinal and circular muscle layers of the gut. Its neurons project to the circular muscle, to other myenteric ganglia, to submucosal ganglia, or directly to the epithelium, and play an important role in regulating and patterning gut motility. (From FASEB J 1989;3:127-38)Locus Coeruleus: Bluish-colored region in the superior angle of the FOURTH VENTRICLE floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the PERIAQUEDUCTAL GRAY.Morphine Derivatives: Analogs or derivatives of morphine.Neurotransmitter Agents: Substances used for their pharmacological actions on any aspect of neurotransmitter systems. Neurotransmitter agents include agonists, antagonists, degradation inhibitors, uptake inhibitors, depleters, precursors, and modulators of receptor function.Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.Neuroblastoma: A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51)Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs.Nociceptive Pain: Dull or sharp aching pain caused by stimulated NOCICEPTORS due to tissue injury, inflammation or diseases. It can be divided into somatic or tissue pain and VISCERAL PAIN.Spinal Cord: A cylindrical column of tissue that lies within the vertebral canal. It is composed of WHITE MATTER and GRAY MATTER.Galanin: A neuropeptide of 29-30 amino acids depending on the species. Galanin is widely distributed throughout the BRAIN; SPINAL CORD; and INTESTINES. There are various subtypes of GALANIN RECEPTORS implicating roles of galanin in regulating FOOD INTAKE; pain perception; memory; and other neuroendocrine functions.Substantia Gelatinosa: Gelatinous-appearing material in the dorsal horn of the spinal cord, consisting chiefly of Golgi type II neurons and some larger nerve cells.Electric Stimulation: Use of electric potential or currents to elicit biological responses.

Dynorphin A processing enzyme: tissue distribution, isolation, and characterization. (1/1136)

Limited proteolysis of the dynorphin precursor (prodynorphin) at dibasic and monobasic processing sites results in the generation of bioactive dynorphins. In the brain and neurointermediate lobe of the pituitary, prodynorphin is processed to produce alpha and beta neo endorphins, dynorphins (Dyn) A-17 and Dyn A-8, Dyn B-13, and leucine-enkephalin. The formation of Dyn A-8 from Dyn A-17 requires a monobasic cleavage between Ile and Arg. We have identified an enzymatic activity capable of processing at this monobasic site in the rat brain and neurointermediate lobe of the bovine pituitary; this enzyme is designated "dynorphin A-17 processing enzyme." In the rat brain and neurointermediate lobe, a majority of the Dyn A processing enzyme activity is membrane-associated and can be released by treatment with 1% Triton X-100. This enzyme has been purified to apparent homogeneity from the membrane extract of the neurointermediate lobe using preparative iso-electrofocussing in a granulated gel pH 3.5 to 10, FPLC using anion exchange chromatography, and non-denaturing electrophoresis. The Dyn A processing enzyme exhibits a pI of about 5.8 and a molecular mass of about 65 kDa under reducing conditions. The Dyn A processing enzyme is a metalloprotease and has a neutral pH optimum. It exhibits substantial sensitivity to metal chelating agents and thiol agents suggesting that this enzyme is a thiol-sensitive metalloprotease. Specific inhibitors of other metallopeptidases such as enkephalinase [EC 3.4.24.11], the enkephalin generating neutral endopeptidase [EC 3.4.24.15], or NRD convertase do not inhibit the Dyn A processing enzyme activity. In contrast, specific inhibitors of angiotensin converting enzyme inhibit the activity. The purified enzyme is able to process a number of neuropeptides at both monobasic and dibasic sites. These characteristics are consistent with a role for the Dyn A processing enzyme in the processing of Dyn A-17 and other neuropeptides in the brain.  (+info)

Binding properties of C-truncated delta opioid receptors. (2/1136)

AIM: To study the role of C-terminal delta opioid receptor involved in ligand binding affinity and selectivity. METHODS: The 31 amino acid residues of C-terminal truncated delta opioid receptors and the wild-type were expressed stably in Chinese hamster ovary (CHO) cells, respectively. Then the ligand binding properties of the products were studied by receptor binding assay. RESULTS: A typical mutated receptor clone CHO-T and a wild-type receptor clone CHO-W were obtained. The Kd values of [3H] diprenorphine (Dip) and [3H]leucine-2-alanine enkephalin (DADLE) bound to CHO-T were similar to CHO-W. Both the specific [3H]Dip bindings of CHO-T and CHO-W were strongly inhibited by delta selective agonists with similar Ki, but neither by mu nor kappa selective agonists. CONCLUSION: The C-terminal of the delta opioid receptor is not involved in the ligands binding affinity and selectivity.  (+info)

Absence of G-protein activation by mu-opioid receptor agonists in the spinal cord of mu-opioid receptor knockout mice. (3/1136)

1. The ability of mu-opioid receptor agonists to activate G-proteins in the spinal cord of mu-opioid receptor knockout mice was examined by monitoring the binding to membranes of the non-hydrolyzable analogue of GTP, guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS). 2. In the receptor binding study, Scatchard analysis of [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin ([3H]DAMGO; mu-opioid receptor ligand) binding revealed that the heterozygous mu-knockout mice displayed approximately 40% reduction in the number of mu-receptors as compared to the wild-type mice. The homozygous mu-knockout mice showed no detectable mu-binding sites. 3. The newly isolated mu-opioid peptides endomorphin-1 and -2, the synthetic selective mu-opioid receptor agonist DAMGO and the prototype of mu-opioid receptor agonist morphine each produced concentration-dependent increases in [35S]GTPgammaS binding in wild-type mice. This stimulation was reduced by 55-70% of the wild-type level in heterozygous, and virtually eliminated in homozygous knockout mice. 4. No differences in the [35S]GTPgammaS binding stimulated by specific delta1- ([D-Pen2,5]enkephalin), delta2-([D-Ala2]deltorphin II) or kappa1-(U50,488H) opioid receptor agonists were noted in mice of any of the three genotypes. 5. The data clearly indicate that mu-opioid receptor gene products play a key role in G-protein activation by endomorphins, DAMGO and morphine in the mouse spinal cord. They support the idea that mu-opioid receptor densities could be rate-limiting steps in the G-protein activation by mu-opioid receptor agonists in the spinal cord. These thus indicate a limited physiological mu-receptor reserve. Furthermore, little change in delta1-, delta2- or kappa1-opioid receptor-G-protein complex appears to accompany mu-opioid receptor gene deletions in this region.  (+info)

Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus. (4/1136)

To test the utility of gene therapeutic approaches for the treatment of pain, a recombinant herpes simplex virus, type 1, has been engineered to contain the cDNA for an opioid peptide precursor, human preproenkephalin, under control of the human cytomegalovirus promoter. This virus and a similar recombinant containing the Escherichia coli lacZ gene were applied to the abraded skin of the dorsal hindpaw of mice. After infection, the presence of beta-galactosidase in neuronal cell bodies of the relevant spinal ganglia (lacZ-containing virus) and of human proenkephalin (preproenkephalin-encoding virus) in the central terminals of these neurons indicated appropriate gene delivery and expression. Baseline foot withdrawal responses to noxious radiant heat mediated by Adelta and C fibers were similar in animals infected with proenkephalin-encoding and beta-galactosidase-encoding viruses. Sensitization of the foot withdrawal response after application of capsaicin (C fibers) or dimethyl sulfoxide (Adelta fibers) observed in control animals was reduced or eliminated in animals infected with the proenkephalin-encoding virus for at least 7 weeks postinfection. Hence, preproenkephalin cDNA delivery selectively blocked hyperalgesia without disrupting baseline sensory neurotransmission. This blockade of sensitization was reversed by administration of the opioid antagonist naloxone, apparently acting in the spinal cord. The results demonstrate that the function of sensory neurons can be selectively altered by viral delivery of a transgene. Because hyperalgesic mechanisms may be important in establishing and maintaining neuropathic and other chronic pain states, this approach may be useful for treatment of chronic pain and hyperalgesia in humans.  (+info)

Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone: in vivo and in vitro characterization of mu-selective agonist and antagonist activity. (5/1136)

Two 14beta-p-nitrocinnamoyl derivatives of dihydrocodeinone, 14beta-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (CACO) and N-cyclopropylmethylnor-14beta-(p-nitrocinnamoylamino)- 7, 8-dihydrocodeinone (N-CPM-CACO), and the corresponding chlorocinnamoylamino analogs, 14beta-(p-chlorocinnamoylamino)-7, 8-dihydrocodeinone (CAM) and N-cyclopropylmethylnor-14beta-(p-chlorocinnamoylamino) -7, 8-dihydrocodeinone (MC-CAM), were tested in opioid receptor binding assays and the mouse tail-flick test to characterize the opioid affinity, selectivity, and antinociceptive properties of these compounds. In competition binding assays, all four compounds bound to the mu opioid receptor with high affinity. When bovine striatal membranes were incubated with any of the four dihydrocodeinones, binding to the mu receptor was inhibited in a concentration-dependent, wash-resistant manner. Saturation binding experiments demonstrated that the wash-resistant inhibition of mu binding was due to a decrease in the Bmax value for the binding of the mu-selective peptide [3H][D-Ala2, MePhe4,Gly(ol)5] enkephalin and not a change in the Kd value, suggesting an irreversible interaction of the compounds with the mu receptor. In the mouse 55 degrees C warm water tail-flick test, both CACO and N-CPM-CACO acted as short-term mu-selective agonists when administered by i. c.v. injection, whereas CAM and MC-CAM produced no measurable antinociception at doses up to 30 nmol. Pretreatment of mice for 24 h with any of the four dihydrocodeinone derivatives produced a dose-dependent antagonism of antinociception mediated by the mu but not the delta or kappa receptors. Long-term antagonism of morphine-induced antinociception lasted for at least 48 h after i.c. v. administration. Finally, shifts in the morphine dose-response lines after 24-h pretreatment with the four dihydrocodeinone compounds suggest that the nitrocinnamoylamino derivatives may produce a greater magnitude long-term antagonism of morphine-induced antinociception than the chlorocinnamoylamino analogs.  (+info)

Effect of phosducin on opioid receptor function. (6/1136)

Phosducin (Phd) regulates the function of G proteins by its ability to tightly bind Gbetagamma subunits. Because the internalization of opioid receptors as well as the activity of adenylyl cyclase (AC) activity depends on G proteins, we tested Phd on these parameters. NG 108-15 hybrid cells stably expressing the phosphoprotein were challenged with [D-penicillamine2,D-penicillamine5]enkephalin to inhibit cAMP generation, demonstrating an increased efficacy of the opioid on AC. Studying the binding of [35S]guanosine-5'-O-(gamma-thio)-triphosphate to membranes from Phd overexpressing cells, we found that [D-penicillamine2, D-penicillamine5 ]enkephalin failed, in the presence of Phd (0.1 nM), to elevate incorporation of the nucleotide. Phd also strongly inhibited opioid-stimulated GTPase activity. NG 108-15 cells were also employed to investigate the effect of Phd on opioid receptor internalization. Control cells and cells overexpressing Phd were transiently transfected to express mu-opioid receptors fused to green fluorescence protein. In controls and in Phd overexpressing cells confocal microscopy identified fluorescence associated with the membrane. Time-lapse series microscopy of living control cells challenged with etorphine (1 microM) revealed receptor internalization within 30 min. In contrast, Phd overexpressing cells largely failed to respond to the opioid. Thus, in Phd overexpressing cells, opioids exhibit an increased efficacy despite the inhibitory action of the phosphoprotein on opioid-stimulated incorporation of [35S]guanosine-5'-O-(gamma-thio)-triphosphate. We suggest that inhibition of GTPase stabilizes the opioid-induced G protein Gi-GTP complex, which is believed to enhance AC inhibition. Finally, scavenging of Gbetagamma by Phd attenuates internalization of opioid receptors, which may contribute to the efficacy of opioids.  (+info)

The absence of a direct correlation between the loss of [D-Ala2, MePhe4,Gly5-ol]Enkephalin inhibition of adenylyl cyclase activity and agonist-induced mu-opioid receptor phosphorylation. (7/1136)

Chronic activation of the mu-opioid receptor (MOR1TAG) results in the loss of agonist response that has been attributed to desensitization and down-regulation of the receptor. It has been suggested that opioid receptor phosphorylation is the mechanism by which this desensitization and down-regulation occurs. When MOR1TAG was stably expressed in both neuroblastoma neuro2A and human embryonic kidney HEK293 cells, the opioid agonist [D-Ala2,MePhe4, Gly5-ol]enkephalin (DAMGO) induced a time- and concentration-dependent phosphorylation of the receptor, in both cell lines, that could be reversed by the antagonist naloxone. Protein kinase C can phosphorylate the receptor, but is not involved in DAMGO-induced MOR1TAG phosphorylation. The rapid rate of receptor phosphorylation, occurring within minutes, did not correlate with the rate of the loss of agonist-mediated inhibition of adenylyl cyclase, which occurs in hours. This lack of correlation between receptor phosphorylation and the loss of response was further demonstrated when receptor phosphorylation was increased by either calyculin A or overexpression of the G-protein receptor kinases. Calyculin A increased the magnitude of MOR1TAG phosphorylation without altering the DAMGO-induced loss of the adenylyl cyclase response. Similarly, when mu- and delta-opioid (DOR1TAG) receptors were expressed in the same system, overexpression of beta-adrenergic receptor kinase 2 elevated agonist-induced phosphorylation for both receptors. However, in the same cell lines under the same conditions, overexpression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 accelerated the rate of DPDPE- but not DAMGO-induced receptor desensitization. Thus, these data show that phosphorylation of MOR1TAG is not an obligatory event for the DAMGO-induced loss in the adenylyl cyclase regulation by the receptor.  (+info)

Antagonism by acetyl-RYYRIK-NH2 of G protein activation in rat brain preparations and of chronotropic effect on rat cardiomyocytes evoked by nociceptin/orphanin FQ. (8/1136)

For the further elucidation of the central functions of nociceptin/orphanin FQ (noc/OFQ), the endogenous ligand of the G protein-coupled opioid receptor-like receptor ORL1, centrally acting specific antagonists will be most helpful. In this study it was found that the hexapeptide acetyl-RYYRIK-NH2 (Ac-RYYRIK-NH2), described in literature as partial agonist on ORL1 transfected in CHO cells, antagonizes the stimulation of [35S]-GTPgammaS binding to G proteins by noc/OFQ in membranes and sections of rat brain. The antagonism of the peptide was competitive, of high affinity (Schild constant 6.58 nM), and specific for noc/OFQ in that the stimulation of GTP binding by agonists for the mu-, delta-, and kappa-opioid receptor was not inhibited. The hexapeptide also fully inhibited the chronotropic effect of noc/OFQ on neonatal rat cardiomyocytes. It is suggested that Ac-RYYRIK-NH2 may provide a promising starting point for in vivo tests for antagonism of the action of noc/OFQ and for the further development of highly active and specific antagonists.  (+info)

  • An enkephalin (occasionally spelt encephalin) is a pentapeptide involved in regulating nociception in the body. (wikipedia.org)
  • Met-enkephalin is a pentapeptide with the amino acid sequence tyr-gly-gly-phe-met. (wikipedia.org)
  • The gas-phase structures of the protonated pentapeptide Leu-enkephalin and its main collision-induced dissociation (CID) product ions, b4 and a4, are investigated by means of infrared multiple-photon dissociation (IR-MPD) spectroscopy and detailed molecular mechanics and density functional theory (DFT) calculations. (meta.org)
  • Enkephalins are found in the thalamus of the brain and in some parts of the spinal cord that transmit pain impulses. (anaspec.com)
  • Computer molecular graphic of part of a molecule of encephalin, a polypeptide found in the human brain. (sciencephoto.com)
  • PES200 will be the second investigational product formulation delivered via the nasal route to enhance enkephalin transport to the brain developed by Virpax. (yahoo.com)
  • PES200 will use a preassembled device and cartridge to propel the enkephalin formulation through the nose to the brain via the olfactory nerve. (yahoo.com)
  • In theory, the Molecular Envelope Technology (MET) will help to carry the enkephalin to the brain to suppress anxiety. (yahoo.com)
  • IR-Met and IR-Leu enkephalin content in the axolotl brain (Ambystoma mexicanum). (semanticscholar.org)
  • Modifications in the distribution of met-enkephalin in the limbic system of the cat brain after electroacupuncture. (semanticscholar.org)
  • These findings indicate that enkephalins competitively inhibit mammalian brain PROT through a direct interaction with the transporter protein at or near the L-proline binding site. (elsevier.com)
  • Enkephalins were the first neuropeptides to be discovered and researched, but that did not happen until the 1970s. (eurekalert.org)
  • Using immunofluorescence and confocal microscopy, we quantified the co-expression of the clock proteins BMAL1 and PER2 with two neuropeptides, Substance P (SubP) and Enkephalin (Enk), expressed in distinct neuronal populations throughout the forebrain. (concordia.ca)
  • Although it is not known exactly how these neuropeptides function, the enkephalins are natural pain killers and may be involved, wth other neuropeptides, in the development of psychopathologic behavior in some cases. (mdbioproducts.com)
  • By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. (diva-portal.org)
  • Olfactory bulbectomy increases prepro-enkephalin mRNA levels in the ventral striatum in rats. (anavex.com)
  • Stable derivative of Leu enkephalin, intravenously administered into rabbits and rats, decreased the rate of activation of creatine phosphokinase, aspartate- and alanine transaminases as well as corrected hypomagnesemia and the deteriorations in blood plasma osmolarity caused by novodrin necrosis of myocardium. (msk.ru)
  • Vinayek, R, Brown, DR & Miller, RJ 1982, ' Tolerance and cross-tolerance to antisecretory action of enkephalins in the guinea-pig ileum ', Gastroenterology , vol. 82, no. 5 II. (northwestern.edu)
  • Plasma Met-enkephalin and catecholamine responses to intense exercise in humans. (thefreedictionary.com)
  • Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. (nih.gov)
  • Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. (nih.gov)
  • The results present evidence of in vivo release of enkephalin-like material in humans and suggest that stimulation analgesia may be partially due to this release. (sciencemag.org)
  • SLepushkin, VD 1984, ' Influence of enkephalins on vasopressin and aldosterone levels in experimental acute myocardial ischemia ', Byulleten Eksperimentalnoi Biologii i Meditsiny , vol. 97, no. 7, pp. 18-19. (elsevier.com)
  • We used immunocytochemistry to study the ontogeny of leu-enkephalin and the catecholamine-synthesizing enzymes dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase in adjacent sections of 14 fetal rhesus and 31 fetal human adrenal glands. (biomedsearch.com)
  • La ĉi-suba teksto estas aŭtomata traduko de la artikolo Leu-enkephalin article en la angla Vikipedio , farita per la sistemo GramTrans on 2016-02-21 11:51:45. (wikitrans.net)
  • Dopamine beta-hydroxylase could be detected at 15 weeks, followed by leu-enkephalin and phenylethanolamine N-methyltransferase at 18-19 weeks. (biomedsearch.com)
  • For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. (nih.gov)
  • In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. (nih.gov)
  • Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. (nih.gov)