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

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.

Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility.

(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.

(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.