methylnaltrexone and Morphine-Dependence

Topics: Analgesics; Animals; Drug Tolerance; Humans; Ketamine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Ondansetron; Pain; Polypharmacy; Quaternary Ammonium Compounds; Serotonin Antagonists

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.

Topics: Animals; Blood-Brain Barrier; Dose-Response Relationship, Drug; Drug Synergism; Infusions, Parenteral; Injections, Subcutaneous; Male; Morphine Dependence; Nalorphine; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Taste

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.

Topics: Animals; Atropine; Biological Transport; Diarrhea; Gastrointestinal Motility; Hexamethonium Compounds; Humans; Intestinal Absorption; Male; Morphine; Morphine Dependence; Naltrexone; Quaternary Ammonium Compounds; Rats; Rats, Inbred Lew; Substance Withdrawal Syndrome; Water-Electrolyte Balance