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Xu Dai - One of the best experts on this subject based on the ideXlab platform.
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Endogenous opioid peptides, endomorphin-1 and -2 and Deltorphin I, stimulate angiogenesis in the CAM assay.
European journal of pharmacology, 2007Co-Authors: Xu Dai, Shi-gang Cui, Ting Wang, Qian Liu, Hong-jin SongAbstract:The opioid peptides modulate extensive bioactivities, including pain, cardiovascular response, development and so on. The effects of endogenous opioid peptides on angiogenesis were evaluated in the chick embryo chorioallantoic membrane (CAM) assay for the first time in the present study. Endomorphin-1, endomorphin-2 and Deltorphin I at the dosage of 1, 10, 100 nmol/embryo could stimulate angiogenesis dose-dependently, respectively. Naloxone, the nonselective opioid receptor antagonist, did not influence angiogenesis alone; but it could antagonize the stimulative effects of the opioid peptides on angiogenesis when it was administrated in combination with the opioid peptides. Taken altogether, the results suggested that endogenous opioid peptides (endomorphin-1 and -2 and Deltorphin I) stimulated angiogenesis in the CAM assay, and these effects were modulated with the opioid receptors. These data are important for potential future clinical implementation.
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melatonin attenuates the development of antinociceptive tolerance to delta but not to mu opioid receptor agonist in mice
Behavioural Brain Research, 2007Co-Authors: Xu Dai, Shi-gang Cui, Qiang Chen, Rui WangAbstract:The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or Deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to Deltorphin I analgesia, and this effect was dose dependent. However. melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of Deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the NIT, receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor. (c) 2007 Elsevier B.V. All rights reserved.
Claire Lacombe - One of the best experts on this subject based on the ideXlab platform.
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Post-translational amino acid racemization in the frog skin peptide Deltorphin I in the secretion granules of cutaneous serous glands.
European journal of cell biology., 2006Co-Authors: Constance Auvynet, Nabila Seddiki, Irene Dunia, Pierre Nicolas, Mohammed Amiche, Claire LacombeAbstract:The dermal glands of the South American hylid frog Phyllomedusa bicolor synthesize and expel huge amounts of cationic, alpha-helical, 24- to 33-residue antimicrobial peptides, the dermaseptins B. These glands also produce a wide array of peptides that are similar to mammalian hormones and neuropeptides, including a heptapeptide opioid containing a d-amino acid, Deltorphin I (Tyr-dAla-Phe-Asp-Val-Val-Gly NH(2)). Its biological activity is due to the racemization of l-Ala2 to d-Ala. The dermaseptins B and Deltorphins are all derived from a single family of precursor polypeptides that have an N-terminal preprosequence that is remarkably well conserved, although the progenitor sequences giving rise to mature opioid or antimicrobial peptides are markedly different. Monoclonal and polyclonal antibodies were used to examine the cellular and ultrastructural distributions of Deltorphin I and dermaseptin B in the serous glands by immunofluoresence confocal microscopy and immunogold-electron microscopy. PreproDeltorphin I and preprodermaseptins B are sorted into the regulated pathway of secretion, where they are processed to give the mature products. Deltorphin I, [l-Ala2]-Deltorphin I and dermaseptin B are all stored together in secretion granules which accumulate in the cytoplasm of all serous glands. We conclude that the l- to d-amino acid isomerization of the Deltorphin I occurs in the secretory granules as a post-translational event. Thus the specificity of isomerization depends on the presence of structural and/or conformational determinants in the peptide N-terminus surrounding the isomerization site.
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peptide secretion in the cutaneous glands of south american tree frog phyllomedusa bicolor an ultrastructural study
European Journal of Cell Biology, 2000Co-Authors: Claire Lacombe, Irene Dunia, Pierre Nicolas, Carmen Cifuentesdiaz, Michele Auberthomay, Mohamed AmicheAbstract:Summary The development of the dermal glands of the arboreal frog Phyllomedusa bicolor was investigated by immunocytochemistry and electron microscopy. The 3 types of glands (mucous, lipid and serous) differed in size and secretory activity. The mucous and serous glands were apparent in the tadpole skin, whereas the lipid glands developed later in ontogenesis. The peptide antibiotics dermaseptins and the D-amino acid-containing peptide opioids dermorphins and Deltorphins are abundant in the skin secretions of P. bicolor . Although these peptides differ in their structure and activity they are derived from precursors that have very similar preproregions. We used an antibody to the common preproregion of preprodermaseptins and preproDeltorphins and immunofluorescence analysis to show that only the serous glands are specifically involved in the biosynthesis and secretion of dermaseptins and Deltorphins. Scanning and transmission electron microscopy revealed that the serous glands of P. bicolor have morphological features, especially the secretory granules, which differ from those of the glands in Xenopus laevis skin.
Raymond C Stevens - One of the best experts on this subject based on the ideXlab platform.
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single amino acid variation underlies species specific sensitivity to amphibian skin derived opioid like peptides
Chemistry & Biology, 2015Co-Authors: Eyal Vardy, Maria F Sassano, Andrew J Rennekamp, Wesley K Kroeze, Philip D Mosier, Richard B Westkaemper, Craig W Stevens, Vsevolod Katritch, Raymond C StevensAbstract:It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and Deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to Deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The Deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides.
Lucia Negri - One of the best experts on this subject based on the ideXlab platform.
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synthesis conformation and biological activity of dermorphin and Deltorphin i analogues containing n alkylglycine in place of residues in position 1 3 5 and 6
Journal of Peptide Science, 2003Co-Authors: Laura Biondi, Lucia Negri, Mauro Marastoni, Roberto Tomatis, Fernando Filira, Elisa Giannini, Marina Gobbo, Barbara Scolaro, Raniero RocchiAbstract:Syntheses are described of new dermorphin and [D-Ala2]Deltorphin I analogues in which the phenylalanine, the tyrosine or the valine residues have been substituted by the corresponding N-alkylglycine residues. Structural investigations by CD measurements in different solvents and preliminary pharmacological experiments were carried out on the resulting peptide-peptoid hybrids. The contribution from aromatic side chain residues is prominent in the CD spectra of dermorphin analogues and the assignment of a prevailing secondary structure could be questionable. In the CD spectra of Deltorphin analogues the aromatic contribution is lower and the dichroic curves indicate the predominance of random conformer populations. The disappearance of the aromatic contribution in the [Ntyr1,D-Ala2]-Deltorphin spectrum could be explained in terms of high conformational freedom of the N-terminal residue. The kinetics of degradation of the synthetic peptoids digestion by rat and human plasma enzymes were compared with that of [Leu5]-enkephalin. The binding to opioid receptors was tested on crude membrane preparations from CHO cells stably transfected with the mu- and delta-opioid receptors. The biological potency of peptoids was compared with that of dermorphin in GPI preparations and with that of Deltorphin I in MVD preparations. All the substitutions produced a dramatic decrease in the affinity of the peptide-peptoid hybrids for both the mu- and delta-opioid receptors. Nval5 and/or Nval6 containing hybrids behaved as mu-opioid receptor agonists and elicit a dose-dependent analgesia (tail-flick test) when injected i.c.v. in rats.
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dermorphin and Deltorphin glycosylated analogues synthesis and antinociceptive activity after systemic administration
Journal of Medicinal Chemistry, 1999Co-Authors: Lucia Negri, Cinzia Severini, Roberta Lattanzi, Barbara Scolaro, Fabio Tabacco, Luigi Orru, Raniero RocchiAbstract:In the present paper we describe the synthesis of some dermorphin and Deltorphin analogues β-O- and α-C-glycosylated on the C-terminal amino acid residue and report their opioid receptor affinity and selectivity as well as their analgesic potency after subcutaneous injection in mice.
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interaction between the μ agonist dermorphin and the δ agonist d ala2 glu4 Deltorphin in supraspinal antinociception and δ opioid receptor binding
British Journal of Pharmacology, 1995Co-Authors: Lucia Negri, Rosa Luisa Potenza, Giovanna Improta, Roberta Lattanzi, F Luchetti, Pietro MelchiorriAbstract:1. In rats, the interaction between the mu-opioid agonist dermorphin and the delta-opioid agonist [D-Ala2, Glu4]Deltorphin was studied in binding experiments to delta-opioid receptors and in the antinociceptive test to radiant heat. 2. When injected i.c.v., doses of [D-Ala2, Glu4]Deltorphin higher than 20 nmol produced antinociception in the rat tail-flick test to radiant heat. Lower doses were inactive. None of the doses tested elicited the maximum achievable response. This partial antinociception was accomplished with an in vivo occupancy of more than 97% of brain delta-opioid receptors and of 17% of mu-opioid receptors. Naloxone (0.1 mg kg-1, s.c.), and naloxonazine (10 mg kg-1, i.v., 24 h before), but not the selective delta-opioid antagonist naltrindole, antagonized the antinociception. 3. In vitro competitive inhibition studies in rat brain membranes showed that [D-Ala2, Glu4]Deltorphin displaced [3H]-naltrindole from two delta-binding sites of high and low affinity. The addition of 100 microM Gpp[NH]p produced a three fold increase in the [D-Ala2, Glu4]Deltorphin Ki value for both binding sites. The addition of 10 nM dermorphin increased the Ki value of the delta-agonist for the high affinity site five times. When Gpp[NH]p was added to the incubation medium together with 10 nM dermorphin, the high affinity Ki of the delta-agonist increased 15 times. 4. Co-administration into the rat brain ventricles of subanalgesic doses of dermorphin and [D-Ala2, Glu4]Deltorphin resulted in synergistic antinociceptive responses. 5. Pretreatment with naloxone or with the non-equilibrium mu-antagonists naloxonazine and beta-funaltrexamine completely abolished the antinociceptive response of the mu-delta agonist combinations. 6. Pretreatment with the delta-opioid antagonists naltrindole and DALCE reduced the antinociceptive response of the dermorphin-[D-Ala2, Glu4]Deltorphin combinations to a value near that observed after the mu-agonist alone. At the dosage used, naltrindole occupied more than 98% of brain delta-opioid receptors without affecting mu-opioid-receptors. 7. These data suggest that in the rat tail-flick test to radiant heat, mu- and delta-opioid agonists co-operate positively in evoking an antinociceptive response. Although interactions between different opioid pathways cannot be excluded, in vitro binding results indicate that this co-operative antinociception is probably mediated by co-activation of the delta-opioid receptors at the cellular level by the mu- and delta-agonist.
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identification and characterization of two dermorphins from skin extracts of the amazonian frog phyllomedusa bicolor
FEBS Letters, 1992Co-Authors: Giuseppina Mignogna, Lucia Negri, Cinzia Severini, Giuliana Falconieri Erspamer, Maurizio Simmaco, Günther Kreil, Donatella BarraAbstract:Skin extracts of South American hylid frogs of the subfamily Phyllomedusinae contain dermorphins and Deltorphins, opioid heptapeptides highly selective for either μ or δ receptors. In all these peptides, a d-amino acid is present in the second position. The structure of the precursors for Ala-Deltorphins was recently deduced from cloned cDNAs derived from skin of Phyllomedusa bicolor (Richter et al. (1990) Proc. Natl. Acad. Sci. USA 87, 4836–4839). From the amino acid sequence of these precursors, the existence of three peptides related to dermorphin could be predicted. From methanol extracts of skin of Ph. bicolor we have isolated two of these peptides. [Lys7]dermorphin-OH and [Trp4,Asn7]dermorphin-OH. The biological activity of these new dermorphins and their amidated counterparts is presented.
Andrew J Rennekamp - One of the best experts on this subject based on the ideXlab platform.
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single amino acid variation underlies species specific sensitivity to amphibian skin derived opioid like peptides
Chemistry & Biology, 2015Co-Authors: Eyal Vardy, Maria F Sassano, Andrew J Rennekamp, Wesley K Kroeze, Philip D Mosier, Richard B Westkaemper, Craig W Stevens, Vsevolod Katritch, Raymond C StevensAbstract:It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and Deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to Deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The Deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides.