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Normalization of small intestinal propulsion with loperamide-like antidiarrheals in rats

1990; Elsevier BV; Volume: 178; Issue: 3 Linguagem: Inglês

10.1016/0014-2999(90)90115-m

1879-0712

Anton A. H. P. Megens, Luc L. J. Canters, F. Awouters, C. J. E. Niemegeers,

Pain Mechanisms and Treatments

Gastrointestinal propulsion and the presence of diarrhea were assessed in rats pretreated with various opioids and challenged orally with either castor or paraffin oil, which both contained phenol red as a marker of gastrointestinal propulsion. In solvent-pretreated rats, diarrhea was always observed within 90 min after castor oil, reflecting a state of hyperpropulsive activity of the gut, but never (up to 8 h) after paraffin oil, reflecting normal intestinal propulsion (which amounted to an average distance of 91% of the total length of the small intestine in 90 min). Paraffin oil propulsion was blocked (to values < 60%) by all opioids tested with the exception of the gut-selective compounds loperamide, loperamide oxide and fluperamide oxide (ED50s: ≥ 160 mg/kg). Castor oil diarrhea was antagonized by all opioids tested and, at comparable but slightly (1.3–2.6 times) higher doses, propulsion was normalized to values (< 100%) comparable to those measured in paraffin oil-challenged control rats. Castor oil propulsion was further reduced to subnormal values (< 60%) by still higher doses of the opioids, comparable to those that blocked propulsion after paraffin oil. However, the required dose increment varied considerably among the opioids tested and ranged, depending on gut selectivity, from a factor 2.3 times the antidiarrheal dose for narcotic analgesics such as pethidine and dextromoramide to > 300 for antidiarrheals such as loperamide, loperamide oxide and fluperamide oxide. Protection from diarrhea and normalization of propulsion showed a close correlation; both failed to correlate with central analgesic activity and are thought to be mediated via peripheral opioid receptors. Blockade of gastrointestinal propulsion after castor oil and paraffin oil was also closely correlated; both activities correlated with analgesia and are thought to be mediated via a central site of action. Apart from affecting motility at the level of or distal to the leo-cecal junction, effects on intestinal fluid transport may play an important role in the mechanism of antidiarrheal action of gut-selective opioids.