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

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 less than 60%) by all opioids tested with the exception of the gut-selective compounds loperamide, loperamide oxide and fluperamide oxide (ED50s: greater than or equal to 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 (less than 100%) comparable to those measured in paraffin oil-challenged control rats. Castor oil propulsion was further reduced to subnormal values (less than 60%) by still higher doses of the opioids, comparable to those that blocked propulsion after paraffin oil. However, the required dose increment varied consistently 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 greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Is in vivo dissociation between the antipropulsive and antidiarrheal properties of opioids in rats related to gut selectivity?

The antipropulsive activity of a series of opioids in the charcoal test was compared with their antidiarrheal activity in the castor oil test and their analgesic activity in the tail withdrawal test. The obtained antipropulsive/antidiarrheal potency ratios varied from 0.71 to greater than 552 [pethidine (oral ED50's in mg/kg: 21.5/30.2), fentanyl (0.77/0.49), dextromoramide (5.39/2.90), methadone (14.2/6.38), codeine (98.4/10.8), morphine (56.6/5.21), diphenoxylate (8.15/0.54), nufenoxole (74.7/1.72), difenoxin (7.10/0.16), loperamide oxide (greater than 160/0.34) and loperamide (greater than 160/0.29)]. The above ratios correlated with the gut selectivity of the compounds as defined by their analgesic/antidiarrheal potency ratios (r = 0.92, P less than 0.001). Furthermore, inhibition of propulsion was found to correlate with central analgesic activity (r = 0.93, P less than 0.001) but not with protection from diarrhea (r = 0.023, P greater than 0.05). Indeed, gut-selective opioids such as loperamide and loperamide oxide failed to affect propulsion up to doses more than 450 times their antidiarrheal doses. In contrast, alpha 2-adrenoceptor agonists delayed propulsion at doses comparable to their antidiarrheal doses [clonidine (0.085 vs 0.021), lidamidine (2.35 vs 1.66)] and anticholinergics inhibited propulsion even at doses many times below their antidiarrheal doses [atropine (0.26 vs 9.30), dexetimide (0.13 vs 5.03) and isopropamide (0.78 vs 74.6)]. The present results indicate that the in vivo inhibition of gastrointestinal propulsion by opioids in rats is mediated by a central action. Effects on intestinal fluid transport or, alternatively, on motility events distal to the ileocecal junction rather than effects on propulsion through the small intestine, seem to be the primary mechanism of antidiarrheal action of gut-selective opioids such as loperamide and loperamide oxide.