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- Title
Orally administered novel cyclic pentapeptide P-317 alleviates symptoms of diarrhoea-predominant irritable bowel syndrome.
- Authors
Zielińska, Marta; Chen, Chunqiu; Mokrowiecka, Anna; Cygankiewicz, Adam I.; Zakrzewski, Piotr K.; Sałaga, Maciej; Małecka‐Panas, Ewa; Wlaź, Piotr; Krajewska, Wanda M.; Fichna, Jakub
- Abstract
Objective The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal ( GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome ( IBS-D). Methods The effect of P-317 on mouse intestinal motility was characterized in vitro and in vivo in physiological and pathopysiological conditions. The antinociceptive action of P-317 was characterized in the mustard oil-induced abdominal pain model and the writhing test. Locomotor activity and grip-strength tests were used to evaluate the effect of P-317 in the central nervous system ( CNS). To translate our study to clinical conditions, the semi-quantitative expression of μ-opioid receptors ( MOP) and κ-opioid receptors ( KOP) messenger RNA ( mRNA) in human colonic samples from IBS-D patients was quantified. Key findings In vitro, P-317 (10−10-10−6 M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, β-funaltrexamine and nor-binaltorphimine-reversible manner. In vivo, P-317 (0.1 mg/kg, i.p. and 1 mg/kg, p.o.) inhibited GI transit, displayed a potent antinociceptive action in abdominal pain tests and did not influence the CNS. Conclusion P-317 produced a potent analgesic and antidiarrhoeal action in the mouse GI tract after oral administration. Given lower expression of MOP and KOP mRNA in IBS-D patients, P-317 is a promising peptide-based drug candidate for IBS-D therapy.
- Subjects
IRRITABLE colon treatment; GASTROINTESTINAL motility; LABORATORY mice; TREATMENT of abdominal pain; PATHOLOGICAL physiology; ANALGESICS
- Publication
Journal of Pharmacy & Pharmacology, 2015, Vol 67, Issue 2, p244
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/jphp.12335