The Enhancing Effects of Peptidase Inhibitors on the Antinociceptive Action of [Met5]Enkephalin-Arg6-Phe7 in Rats

Takahashi, Shigeru; Jin, Xing Lu; Kosaka, Kenya; Yoshikawa, Masanobu; Kobayashi, Hiroyuki; Oka, Tetsuo

doi:10.1254/jphs.fp0070922

Cited by 7 publications

(4 citation statements)

References 10 publications

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“…One possibility is that the reported antagonistic effect of β-end 27 and lack of activity for β-end 26 in vivo is due to the peptides being cleaved to a form that retains affinity but not activity at opioid receptors; most of the studies with these peptides were carried out in the absence of protease inhibitors. However, studies show that peptide activity is greatly increased by the application of protease inhibitors (44,45). Consistent with this, studies carried out to directly test the activity of β-end 27 using [ 35 S]GTPγS binding to C6 membranes expressing μOR showed that this peptide exhibited agonistic activity and this response was not affected by protease blockade (46).…”

Section: Discussionmentioning

confidence: 82%

Biased signaling by endogenous opioid peptides

Gomes

Sierra

Lueptow

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The “Opioid Epidemic” has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([35S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.

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Section: Discussionmentioning

confidence: 82%

Biased signaling by endogenous opioid peptides

Gomes

Sierra

Lueptow

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…accordance with the method in earlier studies by the present group (Kitamura et al, 2000;Takahashi et al, 2007;Akahori et al, 2008;Murata et al, 2014;Ajimi et al, 2015;Matsuda et al, 2017), nociceptive stimulation was achieved by immersing the tail of each rat in hot water (55ºC) for a maximum of 5 sec. This time limit was set to prevent injury to the animal in accordance with the result from earlier studies by the present group showing that persistent pain occurs when the tail is placed in hot water for more than 5 seconds (data not shown).…”

Section: Downloaded Frommentioning

confidence: 99%

Sialorphin Potentiates Effects of [Met⁵]Enkephalin without Toxicity by Action other than Peptidase Inhibition

Kan

Yoshikawa

Watanabe

et al. 2020

J Pharmacol Exp Ther

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This dose-response study investigated the effects of sialorphin on [Met 5 ]enkephalin (ME)-induced inhibition of contractions in mouse vas deferens and antinociception in male rats. Differences were compared among combinations of three chemical peptidase inhibitors: amastatin, captopril, and phosphoramidon. The ratio of potencies of ME in mouse vas deferens pretreated with both sialorphin (100 !M) and a mixture of the three peptidase inhibitors (1 !M each) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration of sialorphin (100 to 400 nmol) significantly and dose-dependently increased ME (3 nmol)-induced antinociception with the mixture of three peptidase inhibitors (10 nmol each). The degree of antinociception with a combination of any two of the peptidase inhibitors (10 nmol each) in the absence of sialorphin was less than that in the presence of sialorphin (200 nmol). Pretreatment with both sialorphin (200 nmol) and the mixture of three peptidase inhibitors (10 nmol each) produced an approximately 100-fold augmentation in ME (10 nmol)-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of DAMGO (D-Ala(2)-N-MePhe(4)-Gly-ol(5)-enkephalin). These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase This article has not been copyedited and formatted. The final version may differ from this version.

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“…It is accepted that C‐terminal amidation is one of the effective strategies to produce potent enkephalin analogues , which some of them produce much stronger analgesia than morphine, as demonstrated in [ d ‐Ala2,MePhe4,Gly]enkephalin amide and Cyclo[Ne,Nb‐carbonyl‐ d ‐Lys2, Dap5]enkephalin amide . Furthermore, because hydrophobic moieties in the C‐terminus could increase tight interactions between enkephalins and the μ ‐opioid receptor binding site , their introduction could result in more potent analgesic analogues such as ME‐Arg‐Gly‐Leu , Tyr‐ d ‐Ala‐Gly‐Phe‐ d ‐Nle‐Arg‐Phe and ME‐Arg6‐Phe7 .…”

Section: Discussionmentioning

confidence: 99%

“…It is reported that hydrophobic moieties on C‐terminus could further enhance antinociceptive effects of enkephalins as well as their binding affinity to opioid receptors . As MEA has been previously identified to possess high biological activity, in this study, the influence of new amide substitutions was examined on its antinociceptive effects and biodegradation by peptidases.…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive effect of [Met5]enkephalin semicarbazide is not affected by dipeptidyl carboxypeptidase‐I

Rezaee

Arabanian

Balalaie

et al. 2011

Journal of Peptide Science

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Dipeptidyl carboxypeptidase-I is an enzyme involved in the biological degradation of enkephalins. It has been suggested that C-terminal amidation of enkephalins enhances their resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation. In this study, a novel [Met5]enkephalin amide (MEA) analogue [Met5]enkephalin (ME)-semicarbazide synthesized by another laboratory in our group was assessed for its antinociceptive effects compared with ME-ethylamide, MEA and ME, using tail flick test. To protect the administered drugs from biodegradation, rats were pretreated with peptidase inhibitors including amastatin, phosphoramidon and captopril. Then captopril (dipeptidyl carboxypeptidase-I inhibitor) was deleted from the peptidase inhibitors' combination for evaluating in vivo resistance of the synthetic drugs to dipeptidyl carboxypeptidase-I. According to the results, ME-semicarbazide and MEA were resistant enough to dipeptidyl carboxypeptidase-I to exert their strong antinociception following intrathecal administration even in the absence of captopril, whereas the antinociceptive effects produced by ME-ethylamide (10 nmol) were abolished in rats not pretreated with captopril, indicating that significant amounts of the ME-ethylamide were degraded by dipeptidyl carboxypeptidase-I. Replacement of the amide moiety of MEA with semicarbazide provides a new ME derivative, with high analgesic effects as well as more resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation.

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The Enhancing Effects of Peptidase Inhibitors on the Antinociceptive Action of [Met5]Enkephalin-Arg6-Phe7 in Rats

Cited by 7 publications

References 10 publications

Biased signaling by endogenous opioid peptides

Biased signaling by endogenous opioid peptides

Sialorphin Potentiates Effects of [Met⁵]Enkephalin without Toxicity by Action other than Peptidase Inhibition

Antinociceptive effect of [Met5]enkephalin semicarbazide is not affected by dipeptidyl carboxypeptidase‐I

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The Enhancing Effects of Peptidase Inhibitors on the Antinociceptive Action of [Met5]Enkephalin-Arg6-Phe7 in Rats

Cited by 7 publications

References 10 publications

Biased signaling by endogenous opioid peptides

Biased signaling by endogenous opioid peptides

Sialorphin Potentiates Effects of [Met5]Enkephalin without Toxicity by Action other than Peptidase Inhibition

Antinociceptive effect of [Met5]enkephalin semicarbazide is not affected by dipeptidyl carboxypeptidase‐I

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Sialorphin Potentiates Effects of [Met⁵]Enkephalin without Toxicity by Action other than Peptidase Inhibition