An antiabsorptive basis for precipitated withdrawal diarrhea in morphine-dependent rats

Diarrhea is a common manifestation of withdrawal from opiates in dependent subjects. This study examined the possibility that this diarrhea results in part from alterations in intestinal fluid transport. Isolated loops of jejunum, ileum and colon were created in morphine-dependent and nondependent rats implanted s.c. with morphine or lactose pellets, respectively. The administration of naltrexone (1 mg/kg s.c.) or its quaternary analog methylnaltrexone (0.01-3 mg/kg i.v.), which does not readily cross the blood-brain barrier, produced a dose-related reduction in fluid absorption from the jejunum and colon of dependent animals only. Similar effects were observed after the i.c.v. injection of quaternary naltrexone (1.0-10 microgram/rat). Both narcotic antagonists, given by any route, produced no change in ileal absorption. Pretreatment with hexamethonium (10 mg/kg i.v.) or atropine (4 mg/kg i.v.) attenuated the antiabsorptive effects of quaternary naltrexone on the jejunum. Serosal addition of naltrexone (10 microM) had no effect on Na or Cl fluxes, short-circuit current or tissue conductance across isolated segments of intestinal mucosa from dependent and nondependent rats. These results indicate that precipitated opiate withdrawal is associated with decreases in jejunal and colonic fluid absorption mediated at sites within both the central nervous system and periphery. Moreover, these effects are not a consequence of a direct opiate action on enterocytes.