Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

Abstract

Background and aims:Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice.Methods:Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques.Results:The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC50 [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively) (P < 0.01). The inhibitory influence of opioid agonists (IC50) in electrically driven ileal mouse preparations were DADLE ([D-Ala2, D-Leu5]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala2, N-Me-Phe4, Glyol5]-enkephalin) > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly κ- and δ-opioid receptor activity with a smaller μ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the μ-opioid receptor antagonists, casoxin 4 and lactoferroxin A, applied before and after morphine injection were unable to antagonize morphine inhibition of gut transit.Conclusions:Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route.

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

“…Casoxin 4 after oral administration failed to attenuate the inhibitory effect of morphine in the murine small intestine. [ 90 ].…”

Role of food-derived opioid peptides in the central nervous and gastrointestinal systems

“…Notably, these gut activities of soymorphins resulted in a dose‐dependent decrease in food intake (anorexigenic activity) in the mice. On the other hand, for opioid antagonistic peptides, casoxin‐4 (Tyr‐Pro‐Ser‐Tyr‐OCH3, a truncated peptide from casoxin A) showed a capability of reversing morphine‐induced inhibition of mouse and guinea pigs ileal contraction in vitro, although it failed to influence morphine‐inhibited mouse small intestinal transit by oral route (Patten, Head, & Abeywardena, ). In addition, casomorphins also exhibited antidiarrhea effect through stimulating the absorption of electrolytes and water in the small intestine (Tomé, Ben Mansour, Hautefeuille, Dumontier, & Desjeux, ).…”

Food-Derived Hemorphins Cross Intestinal and Blood–Brain Barriers In Vitro

“…Hemorphins, from endogenous or food-derived hemoglobin, are found in many different tissues and species ( 1 – 3 ) and many bioactivities have been uncovered for these hemorphins, notably in blood pressure regulation ( 4 – 6 ) and cognitive functions ( 7 ). They were first shown to interact with opioid receptors (ORs) ( 8 , 9 ) that earned them the name “hemorphin,” and explain other activities like intestinal peristalsis ( 10 , 11 ), bladder contraction, inflammation, and pain modulation ( 12 – 14 ). Our laboratory is interested in the fate of alimentary or digested hemoglobin protein and particularly in the derived bioactive peptides thereof in relation to food intake regulation.…”