Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Fabisiak, Adam; Sobocińska, Małgorzata; Kamysz, Elżbieta; Fichna, Jakub; Zielińska, Marta

doi:10.1111/cbdd.13186

Cited by 10 publications

(17 citation statements)

References 31 publications

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“…Noteworthy, the strongest effect among all tested compounds was reported for sialorphin, which was effective already at the lowest balloon distension value (15 mm Hg). In contrast to sialorphin, opiorphin did not evoke any effect on visceral pain …”

Section: Pain Controlmentioning

confidence: 64%

“…Recently our group compared the antinociceptive effect of Leu‐ and Met‐enkephalins (both 1 mg/kg sc ) and two dual NEP/APN inhibitors: sialorphin and opiorphin (1 mg/kg sc ) in the colorectal distension test in mice . Among EEs, only Leu‐enkephalin significantly altered the visceromotor response (VMR) (with the most prominent effect at the highest balloon distension: 60 mm Hg), while Met‐enkephalin remained inactive.…”

Section: Pain Controlmentioning

confidence: 99%

“…In contrast to sialorphin, opiorphin did not evoke any effect on visceral pain. 60 Importantly, enkephalinase inhibitors administered chronically do not induce antinociceptive tolerance and dependence. 61 Noteworthy, in mice treated chronically with RB101 or morphine for 5 consecutive days 2 times a day, the presence of naloxone-induced withdrawal response was evaluated; after sc injection of naloxone on the 6th day, in morphine pretreated group the behavioral changes (ie tremor, wet-dog shakes, jumps, paw shake) and body weight loss were observed.…”

Section: Nep/apn Inhibitorsmentioning

confidence: 99%

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Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders

Szymaszkiewicz

Storr

Fichna

et al. 2018

Neurogastroenterology Motil

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The endogenous opioid system (EOS) is considered being a crucial element involved in the pathophysiology of irritable bowel syndrome (IBS) as it regulates gastrointestinal (GI) homeostasis through modulation of motility and water and ion secretion/absorption. Along with opioid receptors (ORs), the following components of EOS can be distinguished: 1. endogenous opioid peptides (EOPs), namely enkephalins, endorphins, endomorphins and dynorphins, and 2. peptidases, which regulate the metabolism (synthesis and degradation) of EOPs. Enkephalins, which are δ‐opioid receptors agonists, induce significant effects in the GI tract as they act as potent pro‐absorptive neurotransmitters. The action of enkephalins and other EOPs is limited, since EOPs are easily and rapidly inactivated by a natural metalloendopeptidase (enkephalinase/neprilysin) and aminopeptidase N. Studies show that the activity of EOPs can be enhanced by inhibition of these enzymes. In this review, we discuss the antidiarrheal and antinociceptive potential of enkephalinase inhibitors. Furthermore, our review is to answer the question whether enkephalinase inhibitors may be helpful in the future treatment of diarrhea predominant functional GI disorders.

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Section: Pain Controlmentioning

confidence: 64%

Section: Pain Controlmentioning

confidence: 99%

Section: Nep/apn Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders

Szymaszkiewicz

Storr

Fichna

et al. 2018

Neurogastroenterology Motil

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“…19,20 Moreover, prolonged administration of enkephalinase inhibitors is not associated with antinociceptive tolerance. Proof of concept is provided by evidence that enkephalinase inhibition reduces somatic and visceral pain in rodents.…”

Section: Enkephalinase Inhibitionmentioning

confidence: 99%

“…Patients with acute diarrhea reported greater and more sustained reduction in abdominal pain following Racecadotril treatment relative to vehicle 22 or loperamide. 20 It is possible that greater efficacy may be achieved in inflammation-induced models of visceral afferent hypersensitivity or with improved methods of delivery. Whether this reduction was due to an antispasmodic or dampening effect on GI motility, reduced distension due to hypersecretion, or an action on visceral afferents cannot be determined.…”

Section: Enkephalinase Inhibitionmentioning

confidence: 99%

Inflammation without pain: Immune‐derived opioids hold the key

Carbone

Poole

2020

Neurogastroenterology Motil

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Visceral pain is commonly associated with acute or remitting inflammatory bowel disease (IBD). In marked contrast, chronic IBD is often painless, even in the presence of active inflammation. This suggests that inflammation in itself is insufficient to sustain altered nociceptive signaling and raises the possibility that there is an endogenous analgesic system in effect in chronic disease. A new study by Basso et al. published in this issue of Neurogastroenterology & Motility provides additional support for an immune‐mediated mechanism that suppresses visceral hypersensitivity. The authors examined visceral pain in the IL‐10‐piroxicam model of chronic colitis, which differs from other experimental IBD models in that it involves immune suppression. During active inflammation, responses by these mice to graded increases in colorectal distension were equivalent to healthy controls, consistent with normal afferent signaling. However, treatment with a peripherally restricted opioid receptor antagonist resulted in marked visceral hypersensitivity to the same stimuli. This effect was attributed to the production of endogenous opioids by colitogenic CD4+ T cells present in the mucosa. This mini‐review provides a brief overview of analgesia by immune‐derived opioids under inflammatory conditions and highlights how the work of Basso et al. contributes to this area of research. Potential pharmacological approaches to harness or mimic this system are provided. These strategies may prove to be an effective means through which targeted and sustained relief of IBD pain may be achieved.

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1-Substituted sialorphin analogues—synthesis, molecular modelling and in vitro effect on enkephalins degradation by NEP

et al. 2019

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Rat sialorphin (Gln-His-Asn-Pro-Arg) is a natural blocker of neprilysin (NEP) that belongs to the family of endogenous opioid peptide-degrading enzymes. Studies have confirmed the efficiency of sialorphin in blocking the activity of NEP, both in vitro and in vivo. It has been demonstrated that this inhibitor has a strong analgesic, anti-inflammatory, immunological and metabolic effect either directly or indirectly by affecting the level of Met/Leu-enkephalins. In this work, sialorphin and their 12 analogues were synthesised using the solid-phase method. The effect of the peptides on the degradation of Metenkephalin by NEP and metabolic degradation in human plasma was investigated in vitro. We show that the change in the N-terminal amino acid configuration from l to d in almost all peptides, except d-Arg-His-Asn-Pro-Arg (peptide XI), led to the abolition of their inhibitory activity. With molecular modelling technique we explained the structural properties of the l and d-arginine located on the N-terminal part of the peptide. The detailed analysis of the protein binding pocket allowed us to explain why d-arginine is so unique among all d residues. Peptide XI showed the highest stability among the tested peptides in human plasma. For instance sialorphin after a 2-hour incubation in human plasma was almost completely decomposed, while the level of peptide XI dropped to 45% after 48 h under these conditions.

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Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Cited by 10 publications

References 31 publications

Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders

Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders

Inflammation without pain: Immune‐derived opioids hold the key

1-Substituted sialorphin analogues—synthesis, molecular modelling and in vitro effect on enkephalins degradation by NEP

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