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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.


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Effect of double gavage of CSX 4 on morphine inhibition of transit in the SI of the mouse. The dye front represents the percentage of the total length that the dye Poly R-478 has traveled along the length of the SI. The control group (no morphine) was gavaged with saline 20 minutes before the injection of saline subcutaneously, followed 20 minutes later by gavage of dye-containing saline. The morphine group was gavaged with saline 20 minutes before being injected subcutaneously with morphine (2 mg/kg), followed 20 minutes later by gavage of dye. The third group was gavaged with CSX 4 (50 mg/kg) 20 minutes before subcutaneous injection of morphine (2 mg/kg), followed 20 minutes later by gavage of dye containing CSX 4 (50 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM, with the number of mice indicated within the bar. The morphine group and morphine group with CSX 4 were significantly different from the control group (a, ANOVA, P < 0.01). There was no significant difference between the morphine group and the morphine group with CSX 4.Abbreviations: ANOVA, analysis of variance; CSX 4, casoxin 4; SEM, standard error of the mean; SI, small intestine.
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f5-ceg-4-023: Effect of double gavage of CSX 4 on morphine inhibition of transit in the SI of the mouse. The dye front represents the percentage of the total length that the dye Poly R-478 has traveled along the length of the SI. The control group (no morphine) was gavaged with saline 20 minutes before the injection of saline subcutaneously, followed 20 minutes later by gavage of dye-containing saline. The morphine group was gavaged with saline 20 minutes before being injected subcutaneously with morphine (2 mg/kg), followed 20 minutes later by gavage of dye. The third group was gavaged with CSX 4 (50 mg/kg) 20 minutes before subcutaneous injection of morphine (2 mg/kg), followed 20 minutes later by gavage of dye containing CSX 4 (50 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM, with the number of mice indicated within the bar. The morphine group and morphine group with CSX 4 were significantly different from the control group (a, ANOVA, P < 0.01). There was no significant difference between the morphine group and the morphine group with CSX 4.Abbreviations: ANOVA, analysis of variance; CSX 4, casoxin 4; SEM, standard error of the mean; SI, small intestine.

Mentions: Since morphine is also known to increase sphincter tone and inhibit gastric emptying and hence may prevent the gavaged opioid antagonist reaching the small intestine at amounts that could antagonize morphine, a double gavage experiment was designed to potentially overcome this problem.28 However, gavaging the mouse with 50 mg/kg casoxin 4, 20 minutes before injection of 2 mg/kg morphine and 20 minutes after with 50 mg/kg casoxin 4, also failed to significantly reverse the morphine inhibition of gut transit (Figure 5).


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 double gavage of CSX 4 on morphine inhibition of transit in the SI of the mouse. The dye front represents the percentage of the total length that the dye Poly R-478 has traveled along the length of the SI. The control group (no morphine) was gavaged with saline 20 minutes before the injection of saline subcutaneously, followed 20 minutes later by gavage of dye-containing saline. The morphine group was gavaged with saline 20 minutes before being injected subcutaneously with morphine (2 mg/kg), followed 20 minutes later by gavage of dye. The third group was gavaged with CSX 4 (50 mg/kg) 20 minutes before subcutaneous injection of morphine (2 mg/kg), followed 20 minutes later by gavage of dye containing CSX 4 (50 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM, with the number of mice indicated within the bar. The morphine group and morphine group with CSX 4 were significantly different from the control group (a, ANOVA, P < 0.01). There was no significant difference between the morphine group and the morphine group with CSX 4.Abbreviations: ANOVA, analysis of variance; CSX 4, casoxin 4; SEM, standard error of the mean; SI, small intestine.
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f5-ceg-4-023: Effect of double gavage of CSX 4 on morphine inhibition of transit in the SI of the mouse. The dye front represents the percentage of the total length that the dye Poly R-478 has traveled along the length of the SI. The control group (no morphine) was gavaged with saline 20 minutes before the injection of saline subcutaneously, followed 20 minutes later by gavage of dye-containing saline. The morphine group was gavaged with saline 20 minutes before being injected subcutaneously with morphine (2 mg/kg), followed 20 minutes later by gavage of dye. The third group was gavaged with CSX 4 (50 mg/kg) 20 minutes before subcutaneous injection of morphine (2 mg/kg), followed 20 minutes later by gavage of dye containing CSX 4 (50 mg/kg). Total gut transit time was 45 minutes. Results are mean ± SEM, with the number of mice indicated within the bar. The morphine group and morphine group with CSX 4 were significantly different from the control group (a, ANOVA, P < 0.01). There was no significant difference between the morphine group and the morphine group with CSX 4.Abbreviations: ANOVA, analysis of variance; CSX 4, casoxin 4; SEM, standard error of the mean; SI, small intestine.
Mentions: Since morphine is also known to increase sphincter tone and inhibit gastric emptying and hence may prevent the gavaged opioid antagonist reaching the small intestine at amounts that could antagonize morphine, a double gavage experiment was designed to potentially overcome this problem.28 However, gavaging the mouse with 50 mg/kg casoxin 4, 20 minutes before injection of 2 mg/kg morphine and 20 minutes after with 50 mg/kg casoxin 4, also failed to significantly reverse the morphine inhibition of gut transit (Figure 5).

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