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Lucia Negri - One of the best experts on this subject based on the ideXlab platform.
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novel glycosylated lys 7 Dermorphin analogues synthesis biological activity and conformational investigations
Journal of Peptide Science, 2007Co-Authors: Laura Biondi, Lucia Negri, Roberta Lattanzi, Fernando Filira, Elisa Giannini, Marina Gobbo, Raniero RocchiAbstract:Syntheses of the [Lys7]- and [Hyp6,Lys7]-Dermorphin analogues in which either Tyr5 or Hyp6 are O-glucosylated are described. For comparison, the carbohydrate-free peptides have also been prepared. Structural investigations by FT-IR and CD measurements were carried out on the synthetic analogues and some preliminary pharmacological experiments were also performed. The biological potency of the glucosylated analogues was compared with that of the µ-opioid receptor agonist Dermorphin in GPI preparations. Glucosylation of either Tyr5 or Hyp6 reduces the potency of both [Lys7]-Dermorphin and [Hyp6,Lys7]-Dermorphin. The effect induced by the Tyr5 glucosylation is quite strong and the potency of both peptides is reduced by about 150 times. A similar but less dramatic effect is induced by the glucosylation of the Hyp6 residue, and the potency of the parent peptide is reduced by about 15 times. The presence of acetyl groups on the sugar hydroxyl functions further reduces the agonistic potency of the glucosylated analogues. The analgesic potency of [Hyp6,Lys7]-, [Hyp(βGlc)6,Lys7]- and [Tyr(βGlc)5,Lys7]-Dermorphin were also tested in vivo by the tail-flick test. The glucosylated hydroxyproline-containing analogue is 8–10 times less active than the parent peptide, but its analgesic effect lasts significantly longer. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.
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effects of the intravenous administration of lys7 Dermorphin on local cerebral glucose utilization in the rat
European Journal of Pharmacology, 2006Co-Authors: Francesco E Pontieri, Lucia Negri, Roberta Lattanzi, Dario Benincasa, Michele Cavallari, Francesco OrziAbstract:Abstract The use of analgesic opioids in the clinical setting is hampered by the reinforcing and addictive properties of these drugs. Moreover, chronic administration of conventional opioids is accompanied by progressive reduction of the analgesic effects, that often forces clinicians to increase dosages, exposing a subject to serious side-effects. Thus, interest is growing in the development and characterization of synthetic opioid agonists with lower reinforcing properties than conventional opioids. [Lys 7 ]Dermorphin is a μ1 receptor agonist with 20–30 times stronger analgesic properties than morphine. Previous data indicate that the drug causes fewer side-effects than conventional opioids, and is less likely to produce physical dependence than morphine. In this study we investigated the effects of the intravenous administration of a range of doses of [Lys 7 ]Dermorphin (0.002, 0.01 and 0.05 mg/kg) on local cerebral glucose utilization in the rat, by means of the quantitative [ 14 C]2-deoxyglucose method. The results of the study showed dose-related reductions of cerebral metabolic rates for glucose in limbic, sensory-motor and autonomic regions following the intravenous administration of [Lys 7 ]Dermorphin. Such pattern of changes is similar to those measured earlier following the administration of analgesic doses of drugs stimulating μ-opioid receptors. Within the nucleus accumbens, and the shell portion in particular, we did not measure any increase of glucose utilization, rather a significant decrease following the administration of the higher dose of [Lys 7 ]Dermorphin. These findings contribute to the definition of the functional consequences of the administration of [Lys 7 ]Dermorphin, and indirectly suggest the lack of effect of the drug on mesolimbic dopamine neurotransmission.
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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, Roberto Tomatis, Mauro Marastoni, 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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respiratory and cardiovascular effects of the μ opioid receptor agonist lys7 Dermorphin in awake rats
British Journal of Pharmacology, 1998Co-Authors: Lucia Negri, Roberta Lattanzi, Fabio Tabacco, Pietro MelchiorriAbstract:Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]Dermorphin and its main metabolites, [1-5]Dermorphin and [1-4]Dermorphin. Fifteen minutes after injection, doses of [Lys7]Dermorphin producing antinociception (i.c.v., 36–120 nmol; s.c., 0.12–4.7 μmol kg−1) significantly increased respiratory frequency and minute volume of rats breathing air or hypoxic inspirates. This respiratory stimulation was reversed to depression by the 5-HT receptor antagonist ritanserin (2 mg kg−1, s.c.), was blocked by naloxone (0.1 mg kg−1, s.c.), significantly reduced by the μ1 opioid receptor antagonist naloxonazine (10 mg kg−1, s.c., 24 h before) but unaffected by peripherally acting opioid antagonist naloxone methyl bromide (3 mg kg−1, s.c.). Forty five minutes after injection, doses of the peptide producing catalepsy (s.c., 8.3–14.2 μmol kg−1, i.c.v., 360 nmol) significantly reduced respiratory frequency and volume of rats breathing air and blocked the hypercapnic ventilator response of rats breathing from 4% to 10% CO2. I.c.v. administration of [1-5]Dermorphin and [1-4]Dermorphin (from 36 to 360 nmol) never stimulated respiration but significantly reduced basal and CO2-stimulated ventilation. Opioid respiratory depression was only antagonized by naloxone. In awake rats, [Lys7]Dermorphin (0.1–1 mg kg−1, s.c.) decreased blood pressure. This hypotensive response was abolished by naloxone, reduced by naloxone methyl bromide and unaffected by naloxonazine. In conclusion, the present study indicates that analgesic doses of [Lys7]Dermorphin stimulate respiration by activating central μ1 opioid receptors and this respiratory stimulation involves a forebrain 5-hydroxytryptaminergic excitatory pathway.
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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.
Pierre Nicolas - One of the best experts on this subject based on the ideXlab platform.
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structural requirements for Dermorphin opioid receptor binding
International Journal of Peptide and Protein Research, 2009Co-Authors: Mohamed Amiche, Antoine Delfour, Pierre NicolasAbstract:Structural features influencing binding activity of Dermorphin to opioid receptors have been investigated in the rat brain through the synthesis and evaluation of binding affinity of a series of synthetic Dermorphin analogs. Tritiated Dermorphin was used as primary ligand. The single population of high affinity Dermorphin binding sites present in the rat brain is clearly of an opioid nature since bound radiolabeled Dermorphin was fully displaced with high affinity either by morphine or naloxone. Displacement of tritiated Dermorphin by all alkaloid opiates or Dermorphin related peptides tested was monophasic, consistent with simple competitive inhibition at a single population of binding sites. Dermorphin (Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) was the most potent competitor in all experiments. The d-configuration of the amino acid residue in position 2 was found to be of crucial importance for binding. Replacement of d-Ala2 with l-Ala led to a deleterious effect, this analog being 1/5000th as potent as Dermorphin in displacing bound tritiated Dermorphin from its receptor. Shorter Dermorphin homologs, Dermorphin-(1-4)-NH2 and Dermorphin-(1-3)-NH2, were found to be 20 and 40-fold less potent, respectively, than Dermorphin. The C-terminal carboxamide function is of significant importance for manifestation of the full intrinsic binding potency of Dermorphin. Deamidated Dermorphin had 1/5th the potency of the parent peptide. This suggests that while the whole Dermorphin sequence is required for the expression of the full intrinsic binding activity of the molecule, the N-terminal tripeptide is a key structure as it contains the features which allow receptor recognition.
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characterization of the receptor binding profile of 3h Dermorphin in the rat brain
International Journal of Peptide and Protein Research, 2009Co-Authors: Mohamed Amiche, Antoine Delfour, Sandrine Sagan, Amram Mor, Pierre NicolasAbstract:Amphibian skin synthesizes a variety of biologically active peptides. Of these, Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is an extraordinarily potent opioid peptide up to 1000 times more active than morphine in inducing analgesia after intracerebroventricular administration. Dermorphin has little in common with the sequence of all hitherto known mammalian opioid peptides and is unique in having a D-amino acid residue in position 2. Specific binding properties of tritium labeled Dermorphin were characterized in the rat brain. Scatchard or Hill analysis of equilibrium measurements performed over a large range of concentrations revealed a single population of Dermorphin binding sites with a Kd value of 0.46 nM. Dermorphin and the selective mu-receptor ligand (D-Ala2, MePhe4, Gly5-ol)-enkephalin (DAGO) had similar high potencies in competing with (3H)-Dermorphin binding, whereas the inverse holds for the prototypical delta receptor ligand (D-Pen2, D-Pen5)-enkephalin (DPDPE), which exhibited a potency three orders of magnitude lower. Dermorphin was tested for its relative affinity to mu and delta binding sites by determining its potency in displacing (3H)-DAGO and (3H)-DPDPE from rat brain membrane preparations. Based on these comparisons, Dermorphin exhibited a selectivity ratio Ki(DPDPE)/Ki(DAGO) = 100, a value almost identical to that of DAGO, this ligand being considered as the protypical mu-receptor probe. The high affinity and selectivity of (3H)-Dermorphin together with its very low nonspecific binding make this peptide a useful tool for dissecting the role(s) of the mu-receptor(s).
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synthesis and properties of Dermorphin and an analog of β endorphin containing the Dermorphin sequence
International Journal of Peptide and Protein Research, 2009Co-Authors: Donald Yamashiro, Pierre NicolasAbstract:Dermorphin (I) and [D-Ala2, Phe3, Gly4, Tyr5, Pro6]-beta c-EP (II) have been synthesized by the solid-phase method (beta c-EP, camel beta-endorphin). Positions 1 through 7 of II correspond to the sequence of I. Relative potencies of synthetic peptides in the mouse tail-flick test for analgesia by the intracerebroventricular route were: human beta-endorphin, 100; camel beta-endorphin, 164; I, 450; II, 440. The Dermorphin was about 670 times more potent than morphine in the assay. Peptide II represents a rare instance where the enkephalin moiety of beta-endorphin has been altered to produce a more potent analgesic.
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phylloxin a novel peptide antibiotic of the dermaseptin family of antimicrobial opioid peptide precursors
FEBS Journal, 2000Co-Authors: Thierry Nicolas Pierre, Mohamed Amiche, Aura Lia A Seon, Pierre NicolasAbstract:A novel family of peptide precursors that have very similar N-terminal preprosequences followed by markedly different C-terminal domains has been identified in the skin of hylid frogs belonging to the genus Phyllomedusinae. Biologically active peptides derived from the variable domains include the dermaseptins, 28–34-residue peptides that have a broad-spectrum microbicidal activity, and Dermorphin and the deltorphins, d-amino acid containing heptapeptides that are very potent agonists for the µ-opioid and δ-opioid receptors, respectively. This report describes the isolation, synthesis and cloning of phylloxin, a prototypical member of a novel family of antimicrobial peptides derived from the processing of a dermaseptin/Dermorphin-like precursor. The structure of phylloxin (GWMSKIASGIGTFLSGIQQ amide) shows no homology to the dermaseptins, but bears some resemblance to the levitide-precursor fragment and the xenopsin-precursor fragment, two antimicrobial peptides isolated from the skin of an evolutionarily distant frog species, Xenopus laevis. Circular dichroism spectra of phylloxin in low polarity medium, which mimics the lipophilicity of the membrane of target microorganisms, indicated 60–70% α-helical conformation, and predictions of secondary structure suggested that the peptide can be configured as an amphipathic helix spanning residues 1–19. Phylloxin is an addition to the structurally and functionally diverse peptide families encoded by the rapidly evolving C-terminal domains of the Dermorphin/dermaseptin group of precursors.
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identification of a d alanine containing polypeptide precursor for the peptide opioid Dermorphin
Journal of Biological Chemistry, 1991Co-Authors: Amram Mor, Antoine Delfour, Pierre NicolasAbstract:The naturally occurring amphibian skin peptides Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) are highly potent and selective agonists at the mu- and the delta-opioid receptors, respectively. For peptides synthesized by animal cells, they have a rather peculiar structural feature of containing a D-amino acid residue in their sequence which imparts biological activity on them. The cloned cDNA encoding the proDermorphin precursor contains the usual alanine and methionine codons at positions where D-alanine and D-methionine are present in the mature products. In this study, Dermorphin precursor was characterized in extracts from amphibian skin by antisera recognizing distinct epitopes within the predicted structure of pro-Dermorphin. Proteolytic digestion of purified endogenous pro-Dermorphin generated a peptide containing a D-alanine in position 2, identified as prepro-Dermorphin-(80-89), i.e. Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-Gly-Glu-Ala. In addition, analysis of skin extracts by enzyme immunoassays coupled to high performance liquid chromatography separations revealed the presence of, besides dermenkephalin, novel dermenkephalin-related peptides, i.e. [L-Met2]dermenkephalin, dermenkephalin-OH, and [Met(O)6]dermenkephalin. [L-Met2]dermenkephalin was present in frog skin in a concentration of about 100 times that of dermenkephalin. These observations confirm that, despite the presence of D-amino acid residues, Dermorphin and dermenkephalin are genuine products of post-translational processing of a ribosomally made precursor. They suggest that D-Ala and D-Met develop from a dehydrogenation/hydrogenation stereoinversion of their corresponding L isomers incorporated into pro-Dermorphin, a process that occurs with low efficiency at an early stage of biosynthesis.
Pietro Melchiorri - One of the best experts on this subject based on the ideXlab platform.
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respiratory and cardiovascular effects of the μ opioid receptor agonist lys7 Dermorphin in awake rats
British Journal of Pharmacology, 1998Co-Authors: Lucia Negri, Roberta Lattanzi, Fabio Tabacco, Pietro MelchiorriAbstract:Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]Dermorphin and its main metabolites, [1-5]Dermorphin and [1-4]Dermorphin. Fifteen minutes after injection, doses of [Lys7]Dermorphin producing antinociception (i.c.v., 36–120 nmol; s.c., 0.12–4.7 μmol kg−1) significantly increased respiratory frequency and minute volume of rats breathing air or hypoxic inspirates. This respiratory stimulation was reversed to depression by the 5-HT receptor antagonist ritanserin (2 mg kg−1, s.c.), was blocked by naloxone (0.1 mg kg−1, s.c.), significantly reduced by the μ1 opioid receptor antagonist naloxonazine (10 mg kg−1, s.c., 24 h before) but unaffected by peripherally acting opioid antagonist naloxone methyl bromide (3 mg kg−1, s.c.). Forty five minutes after injection, doses of the peptide producing catalepsy (s.c., 8.3–14.2 μmol kg−1, i.c.v., 360 nmol) significantly reduced respiratory frequency and volume of rats breathing air and blocked the hypercapnic ventilator response of rats breathing from 4% to 10% CO2. I.c.v. administration of [1-5]Dermorphin and [1-4]Dermorphin (from 36 to 360 nmol) never stimulated respiration but significantly reduced basal and CO2-stimulated ventilation. Opioid respiratory depression was only antagonized by naloxone. In awake rats, [Lys7]Dermorphin (0.1–1 mg kg−1, s.c.) decreased blood pressure. This hypotensive response was abolished by naloxone, reduced by naloxone methyl bromide and unaffected by naloxonazine. In conclusion, the present study indicates that analgesic doses of [Lys7]Dermorphin stimulate respiration by activating central μ1 opioid receptors and this respiratory stimulation involves a forebrain 5-hydroxytryptaminergic excitatory pathway.
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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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production of antinociception by peripheral administration of lys7 Dermorphin a naturally occurring peptide with high affinity for μ opioid receptors
British Journal of Pharmacology, 1995Co-Authors: Lucia Negri, Roberta Lattanzi, Pietro MelchiorriAbstract:1. The opioid activity of the amphibian peptide, [Lys7]Dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]Dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]Dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]Dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]Dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]Dermorphin-dependent mice. 7. In conclusion, [Lys7]Dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.
Frank Porreca - One of the best experts on this subject based on the ideXlab platform.
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descending facilitation from the rostral ventromedial medulla maintains nerve injury induced central sensitization
Neuroscience, 2006Co-Authors: Louis P Veraportocarrero, En Tan Zhang, Tamara King, Michael H Ossipov, Frank PorrecaAbstract:Nerve injury can produce hypersensitivity to noxious and normally innocuous stimulation. Injury-induced central (i.e. spinal) sensitization is thought to arise from enhanced afferent input to the spinal cord and to be critical for expression of behavioral hypersensitivity. Descending facilitatory influences from the rostral ventromedial medulla have been suggested to also be critical for the maintenance, though not the initiation, of experimental neuropathic pain. The possibility that descending facilitation from the rostral ventromedial medulla is required for the maintenance of central sensitization was examined by determining whether ablation of mu-opioid receptor-expressing cells within the rostral ventromedial medulla prevented the enhanced expression of repetitive touch-evoked FOS within the spinal cord of animals with spinal nerve ligation injury as well as nerve injury-induced behavioral hypersensitivity. Rats received a single microinjection of vehicle, saporin, Dermorphin or Dermorphin-saporin into the rostral ventromedial medulla and 28 days later, underwent either sham or spinal nerve ligation procedures. Animals receiving rostral ventromedial medulla pretreatment with vehicle, Dermorphin or saporin that were subjected to spinal nerve ligation demonstrated both thermal and tactile hypersensitivity, and showed significantly increased expression of touch-evoked FOS in the dorsal horn ipsilateral to nerve injury compared with sham-operated controls at days 3, 5 or 10 post-spinal nerve ligation. In contrast, nerve-injured animals pretreated with Dermorphin-saporin showed enhanced behaviors and touch-evoked FOS expression in the spinal dorsal horn at day 3, but not days 5 and 10, post-spinal nerve ligation when compared with sham-operated controls. These results indicate the presence of nerve injury-induced behavioral hypersensitivity associated with nerve injury-induced central sensitization. Further, the results demonstrate the novel concept that once initiated, maintenance of nerve injury-induced central sensitization in the spinal dorsal horn requires descending pain facilitation mechanisms arising from the rostral ventromedial medulla.
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Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor
2001Co-Authors: Frank Porreca, Michael H Ossipov, Shannon E. Burgess, Luis R. Gardell, Todd W., Philip T. Malan, Josephine LaiAbstract:Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing �-opioid receptors were targeted with a single microinjection of saporin conjugated to the �-opioid agonist Dermorphin; unconjugated saporin and Dermorphin were used as controls. RVM Dermorphin–saporin, but not Dermorphin or saporin, significantly decreased cells expressing �-opioid receptor transcript. RVM Dermorphin, saporin, or Dermorphin–saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM Dermorphin–saporin failed to elicit the expected increase i
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the synthesis and opioid receptor binding affinities of analogues of Dermorphin and its n terminal tetrapeptide fragment with dibasic acids in position 2
Life Sciences, 1995Co-Authors: Frank Porreca, Andrzej W Lipkowski, Aleksandra Misicka, Henry I Yamamura, Jirina Slaninova, Peg Davis, Victor J HrubyAbstract:Abstract Analysis of possible μ opioid receptor active conformations for Dermorphin suggested that the topographical location of the tyramine moiety of the N-tenninal tyrosine can be simulated with the phenol of tyrosine 1 or desamino-tyrosine 1 (4-hydroxyphenylpropionic acid) and a basic group located on the side chain of a dibasic acid residue located in position 2. The biological properties of respective analogs with D- or L-arginine, and D- or L-lysine in the position 2 of Dermorphin or desaminoDermorphin and their N-terminal tetrapeptide fragments, has provided evidence in support of this prediction, and questions the dogma that an N-terminal tyrosine is a necessary element for opioid agonist peptides.
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Dermorphin sequence with high δ afinity by fixing the phe sidechain to trans at ξ1
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Dirk Tourwe, Frank Porreca, Peg Davis, K Verschueren, G Van Binst, Victor J HrubyAbstract:Abstract The Phe sidechain in Dermorphin was fixed into the trans conformation by linking the aromatic ring to the Gly nitrogen through a methylene bridge. The compound has high μ- and δ-opioid activities.
Aleksandra Misicka - One of the best experts on this subject based on the ideXlab platform.
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synthesis binding affinities and metabolic stability of dimeric Dermorphin analogs modified with β3 homo amino acids
Journal of Peptide Science, 2016Co-Authors: Oliwia Frączak, Aleksandra Misicka, Anika Lasota, Dagmara Tymecka, Piotr Kosson, Adriana Muchowska, Aleksandra OlmaAbstract:In this study, proteinogenic amino acids residues of dimeric Dermorphin pentapeptides were replaced by the corresponding β(3)-homo-amino acids. The potency and selectivity of hybrid α/β dimeric Dermorphin pentapeptides were evaluated by competetive receptor binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). Tha analog containing β(3)-homo-Tyr in place of Tyr (Tyr-D-Ala-Phe-Gly-β(3)-homo-Tyr-NH-)2 showed good μ receptor affinity and selectivity (IC50 = 0.302, IC50 ratio μ/δ = 68) and enzymatic stability in human plasma.
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synthesis and biological properties of gamma glutamyl Dermorphin a prodrug
Life Sciences, 1996Co-Authors: Andrzej W Lipkowski, Aleksandra Misicka, Iwona Maszczynska, Dagmar Stropova, Henry I Yamamura, Victor J HrubyAbstract:Abstract The possibility of using the gamma-glutamyl-transpeptidase system for transformation of inactive propeptide, gamma-glutamyl-neuropeptides into active neuropeptides has been tested on Dermorphin and its gamma-glutamyl analogue. Gamma-glutamyl-Dermorphin 2 showed little affinity for opioid receptors. Nonetheless, systemic (intraperitoneal (i.p.), or intravenous (i.v.)) application of this compound induced significant antinociceptive effects, although ten to twenty-fold higher doses were required compared to the parent Dermorphin 1. On the other hand, the analogue 2 showed high, antinociceptive activity when injected intrathecally (i.t.). When compared to Dermorphin, 2 was one third as potent, but did show a significant prolonged duration of the effect. These results suggest that in the periphery, the peptidase metabolism which results in degradation of bioactivity, is offset by gammaglutamyl transpeptidase (GGTP) activity that liberates bioactive peptide 2. On the other hand, in the central nervous system, the activity of gamma-glutamyl-transpeptidase system seems to be more effective than other peptidase systems, resulting in formation of active peptide 2 in a significant amount. These data suggests that gamma-glutamyl analogues of neuropeptides can be considered as potential prodrugs, especially for synthetic analogues which themselves are resistant to peptidase action.
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the synthesis and opioid receptor binding affinities of analogues of Dermorphin and its n terminal tetrapeptide fragment with dibasic acids in position 2
Life Sciences, 1995Co-Authors: Frank Porreca, Andrzej W Lipkowski, Aleksandra Misicka, Henry I Yamamura, Jirina Slaninova, Peg Davis, Victor J HrubyAbstract:Abstract Analysis of possible μ opioid receptor active conformations for Dermorphin suggested that the topographical location of the tyramine moiety of the N-tenninal tyrosine can be simulated with the phenol of tyrosine 1 or desamino-tyrosine 1 (4-hydroxyphenylpropionic acid) and a basic group located on the side chain of a dibasic acid residue located in position 2. The biological properties of respective analogs with D- or L-arginine, and D- or L-lysine in the position 2 of Dermorphin or desaminoDermorphin and their N-terminal tetrapeptide fragments, has provided evidence in support of this prediction, and questions the dogma that an N-terminal tyrosine is a necessary element for opioid agonist peptides.