Supraspinal inhibitory effects of chimeric peptide MCRT on gastrointestinal motility in mice

Author:

He Chunbo1,Li Hailan1,Zhang Jing1,Kang Yanping1,Jia Fang1,Dong Shouliang12,Zhou Lanxia34

Affiliation:

1. Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, China

2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, China

3. The Core Laboratory of the First Affiliated Hospital, Lanzhou University, Lanzhou, China

4. Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou, China

Abstract

Abstract Objectives Chimeric peptide MCRT, based on morphiceptin and PFRTic-NH2, was a bifunctional ligand of μ- and δ-opioid receptors (MOR-DOR) and produced potent analgesia in tail-withdrawal test. The study focused on the supraspinal effects of morphiceptin, PFRTic-NH2 and MCRT on gastrointestinal motility. Moreover, opioid receptor antagonists, naloxone (non-selective), cyprodime (MOR selective) and naltrindole (DOR selective) were utilized to explore the mechanisms. Methods Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility. Key findings (1) At supraspinal level, morphiceptin, PFRTic-NH2 and MCRT significantly decreased gastric emptying and intestinal transit; (2) MCRT at 1 nmol/mouse, far higher than its analgesic dose (ED50 = 29.8 pmol/mouse), failed to regulate the gastrointestinal motility; (3) MCRT-induced gastrointestinal dysfunction could be completely blocked by naloxone and naltrindole, but not affected by cyprodime. Conclusions (1) Morphiceptin and PFRTic-NH2 played important roles in the regulation of gastrointestinal motility; (2) MCRT possessed higher bioactivity of pain relief than gastrointestinal regulation, suggesting its promising analgesic property; (3) MCRT-induced motility disorders were sensitive to DOR but not to MOR blockade, indicating the pain-relieving specificity of speculated MOR subtype or splice variant or MOR-DOR heterodimer.

Funder

Fundamental Research Funds for the Central Universities

Foundation of Key Laboratory for Gastrointestinal Diseases of Gansu Province

Health Industry Research Project of Gansu Province

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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