Structure-activity relationships of the δ-opioid-selective agonists, deltorphins

Melchiorri, Pietro; Negri, Lucia; Falconieri–Erspamer, Giuliana; Severini, Cinzia; Corsi, Rita; Soaje, Marta; Erspamer, V.; Barra, Donatella

doi:10.1016/0014-2999(91)90536-y

Cited by 72 publications

(60 citation statements)

References 15 publications

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“…The specificity of dermorphin-saporin for RVM cells expressing -opioid receptors was confirmed by the use of ␤-FNA, a selective and irreversible -opioid receptor antagonist (Ward et al, 1982;Jiang et al, 1990). RVM microinjection of ␤-FNA was shown to antagonize the antinociceptive effects of a receptor-selective opioid , but not selective ␦ or , agonist indicating that the dose administered selectively blocked -opioid receptors; the selectivity of the antagonist is supported by similar results in previous studies (Tiberi et al, 1988;Melchiorri et al, 1991). Administration of RVM dermorphin-saporin in rats pretreated with ␤-FNA showed that the expected prevention of nerve injury-induced pain was blocked; ␤-FNA pretreatment did not alter the development of nerve injury-induced pain in groups pretreated with either dermorphin or saporin.…”

Section: Discussionsupporting

confidence: 71%

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

et al. 2001

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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 in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin-saporin against SNL-induced pain was blocked by ␤-funaltrexamine, a selective -opioid receptor antagonist, indicating specific interaction of dermorphin-saporin with the -opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.

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Section: Discussionsupporting

confidence: 71%

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

et al. 2001

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“…The IC 50 values obtained in preparations from wild-type mice were 13.89 Ϯ 2.16 nM for DPDPE and 1.87 Ϯ 0.30 nM for deltorphin II. A similar activity profile of the two agonists was reported previously in Albino Swiss mice (Melchiorri et al, 1991), although vas deferens preparations from this mouse strain were more responsive to ␦-opioid agonists than those from hybrid 129/SV x C57Bl/6 mice used in the present study. In mutant mice, IC 50 values were 22.44 Ϯ 4.59 nM for DPDPE and 3.85 Ϯ 0.90 nM for deltorphin II.…”

Section: Inhibition Of the Vas Deferens Twitch In Mor-deficient Micesupporting

confidence: 66%

Activity of the δ-Opioid Receptor Is Partially Reduced, Whereas Activity of the κ-Receptor Is Maintained in Mice Lacking the μ-Receptor

et al. 1998

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Previous pharmacological studies have indicated the possible existence of functional interactions between -, ␦-and -opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of ␦-and -opioid receptors in mice lacking the -opioid receptor (MOR). Measurements of agonist-induced [ ] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR Ϫ/Ϫ mice. ␦-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR Ϫ/Ϫ mice. Analgesic and respiratory responses produced by the selective -agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of ␦-and -receptor signaling properties in mice lacking -receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the -agonist further suggest that the -receptor mainly acts independently from the -receptor in vivo. Reduced ␦-analgesia and the absence of ␦-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between -receptors and central ␦-receptors in specific neuronal pathways.

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“…Provided that the &receptor selectivity of deltorphin-I1 is primarily based on the molecular conformations of this peptide and not on other factors such as hydrophobicity or hydrophilicity, it may be that the turn conformation of the C-terminal tripeptide, which is detached from the helically folded conformation of the N-terminal tetrapeptide, plays an important role in discriminating the @&selectivity, because the N-terminal peptide of p-selective dermorphin (Tyr-D-AlaPhe-Gly-Tyr-Pro-Ser-NH,) has been reported to take a similar folded conformation [22]. Similar conclusions have also been reached by other groups [15, 20,34,[36][37][38]. This suggests that the message-address concept proposed by Schwyzer [39] is a useful approach for understanding the structuralkonformational characteristics of the receptorselective opioid [40,411 in such a way that the opioid is recognized by a message subsite of the receptor and its selectivity is dominated by interaction with the address subsite.…”

Section: Conformational Relationship With P/d-selectivitysupporting

confidence: 73%

Conformation of deltorphin‐II in membrane environment studied by two‐dimensional NMR spectroscopy and molecular dynamics calculations

Ohno

Segawa

Ohishi

et al. 1993

European Journal of Biochemistry

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Two-dimensional homonuclear Hartmann-Hahn spectroscopy and NOESY (nuclear Overhauser effect and exchange spectroscopy) 'H-NMR techniques have been used to obtain complete proton resonance assignments and to perform a conformational investigation of deltorphin-I1 (Tyr-D-AlaPhe-Glu-Val-Val-Gly-NH,), a naturally occurring &selective opioid peptide, in the membrane-mimetic micelles of perdeuterated dodecylphosphocholine. This was done in order to examine conformational characteristics that would be closely related to the selectivity towards the 8-opioid receptor. With the use of the proton-proton distances derived from NOESY measurements, 50 possible threedimensional structures were generated by means of distance-geometry calculations, and 25 of them were subjected to the molecular-dynamics simulations of 10 ps, which were energetically constrained for the NOE interproton distances. Most of the possible conformers simulated showed a common feature such that the conformation of deltorphin-I1 is characterized by the S-shaped backbone structure in which the turn conformation of the Val-Val-Gly-NH, sequence is located under the helically folded conformation of the N-terminal Tyr-D-Ala-Phe-Glu sequence. The possible relationship between this conformational characteristic and the 6-opioid-receptor selectivity has been discussed.

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Structure-activity relationships of the δ-opioid-selective agonists, deltorphins

Cited by 72 publications

References 15 publications

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

Activity of the δ-Opioid Receptor Is Partially Reduced, Whereas Activity of the κ-Receptor Is Maintained in Mice Lacking the μ-Receptor

Conformation of deltorphin‐II in membrane environment studied by two‐dimensional NMR spectroscopy and molecular dynamics calculations

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