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

Patten GS, Head RJ, Abeywardena MY - Clin Exp Gastroenterol (2011)

Bottom Line: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients.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.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.

View Article: PubMed Central - PubMed

Affiliation: CSIRO Preventative Health National Research Flagship, Adelaide, Australia;

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 (IC(50) [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 (IC(50)) in electrically driven ileal mouse preparations were DADLE ([D-Ala(2), D-Leu(5)]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala(2), N-Me-Phe(4), Glyol(5)]-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.

No MeSH data available.


Related in: MedlinePlus

Effect of naloxone subcutaneously or orally on morphine inhibition of transit in SI of the mouse. The dye front represents the percentage of the total SI that the dye Poly R-478 has traveled along the length of the SI. Saline alone, or morphine (2 mg/kg), or morphine plus naloxone (2 mg/kg each) were injected subcutaneously 20 minutes before the gavage of dye ± naloxone (15 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM with the number of mice indicated inside the bar. Morphine at 2 mg/kg significantly inhibited transit (a, ANOVA, P < 0.01) compared with control as 0 mg/kg morphine. Treatment with morphine with naloxone added subcutaneously or with morphine at the same time as gavage of dye (orally) were significantly different from morphine treatment alone (2 mg/kg) (P < 0.01) but not significantly different from control as 0 mg/kg morphine.Abbreviations: ANOVA, analysis of variance; p.o., orally; s.c., subcutaneously; SEM, standard error of the mean; SI, small intestine.
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f6-ceg-4-023: Effect of naloxone subcutaneously or orally on morphine inhibition of transit in SI of the mouse. The dye front represents the percentage of the total SI that the dye Poly R-478 has traveled along the length of the SI. Saline alone, or morphine (2 mg/kg), or morphine plus naloxone (2 mg/kg each) were injected subcutaneously 20 minutes before the gavage of dye ± naloxone (15 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM with the number of mice indicated inside the bar. Morphine at 2 mg/kg significantly inhibited transit (a, ANOVA, P < 0.01) compared with control as 0 mg/kg morphine. Treatment with morphine with naloxone added subcutaneously or with morphine at the same time as gavage of dye (orally) were significantly different from morphine treatment alone (2 mg/kg) (P < 0.01) but not significantly different from control as 0 mg/kg morphine.Abbreviations: ANOVA, analysis of variance; p.o., orally; s.c., subcutaneously; SEM, standard error of the mean; SI, small intestine.

Mentions: The alkaloid opioid antagonist naloxone, however, significantly reversed the morphine inhibition of mouse gut transit when added either subcutaneously with morphine or orally 20 minutes after subcutaneous injection of morphine gavaged with the Poly R-478 (Figure 6).


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

Patten GS, Head RJ, Abeywardena MY - Clin Exp Gastroenterol (2011)

Effect of naloxone subcutaneously or orally on morphine inhibition of transit in SI of the mouse. The dye front represents the percentage of the total SI that the dye Poly R-478 has traveled along the length of the SI. Saline alone, or morphine (2 mg/kg), or morphine plus naloxone (2 mg/kg each) were injected subcutaneously 20 minutes before the gavage of dye ± naloxone (15 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM with the number of mice indicated inside the bar. Morphine at 2 mg/kg significantly inhibited transit (a, ANOVA, P < 0.01) compared with control as 0 mg/kg morphine. Treatment with morphine with naloxone added subcutaneously or with morphine at the same time as gavage of dye (orally) were significantly different from morphine treatment alone (2 mg/kg) (P < 0.01) but not significantly different from control as 0 mg/kg morphine.Abbreviations: ANOVA, analysis of variance; p.o., orally; s.c., subcutaneously; SEM, standard error of the mean; SI, small intestine.
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Related In: Results  -  Collection

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f6-ceg-4-023: Effect of naloxone subcutaneously or orally on morphine inhibition of transit in SI of the mouse. The dye front represents the percentage of the total SI that the dye Poly R-478 has traveled along the length of the SI. Saline alone, or morphine (2 mg/kg), or morphine plus naloxone (2 mg/kg each) were injected subcutaneously 20 minutes before the gavage of dye ± naloxone (15 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM with the number of mice indicated inside the bar. Morphine at 2 mg/kg significantly inhibited transit (a, ANOVA, P < 0.01) compared with control as 0 mg/kg morphine. Treatment with morphine with naloxone added subcutaneously or with morphine at the same time as gavage of dye (orally) were significantly different from morphine treatment alone (2 mg/kg) (P < 0.01) but not significantly different from control as 0 mg/kg morphine.Abbreviations: ANOVA, analysis of variance; p.o., orally; s.c., subcutaneously; SEM, standard error of the mean; SI, small intestine.
Mentions: The alkaloid opioid antagonist naloxone, however, significantly reversed the morphine inhibition of mouse gut transit when added either subcutaneously with morphine or orally 20 minutes after subcutaneous injection of morphine gavaged with the Poly R-478 (Figure 6).

Bottom Line: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients.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.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.

View Article: PubMed Central - PubMed

Affiliation: CSIRO Preventative Health National Research Flagship, Adelaide, Australia;

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 (IC(50) [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 (IC(50)) in electrically driven ileal mouse preparations were DADLE ([D-Ala(2), D-Leu(5)]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala(2), N-Me-Phe(4), Glyol(5)]-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.

No MeSH data available.


Related in: MedlinePlus