Antidiarrheal properties of supraspinal mu and delta and peripheral mu, delta and kappa opioid receptors: Inhibition of diarrhea without constipation

J. E. Shook, P. K. Lemcke, C. A. Gehrig, V. J. Hruby, T. F. Burks

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We evaluated the ability of mu [morphine, Tyr-Pro-N-MePhe-D-Pro-NH2 (PLO17)], delta (Tyr-D-Pen-Gly-Phe-D-Pen) (DPDPE) and kappa [U50,488H, (trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclo- hexyl)benzeneacetamine)] opioid receptor selective agonists to inhibit diarrhea induced by castor oil (0.6 ml p.o.) in mice after supraspinal (i.c.v.) and peripheral (s.c.) administration. The antidiarrheal potency of each compound was compared to its analgesic and gastrointestinal antitransit potency when given by the same route of administration. When administered i.c.v. morphine, PLO17 and DPDPE inhibited diarrhea in a dose-related fashion. The mu agonists, morphine and PLO17, given i.c.v., inhibited diarrhea at doses much lower than those needed to produce analgesia or to inhibit gastrointestinal transit. DPDPE (i.c.v.) was equipotent in inhibiting diarrhea and in eliciting analgesia, but did not effect the rate of transit. U50,488H (i.c.v.) inhibited diarrhea only at extremely high doses which also caused profound postural-motor incapacitance. U50,488H given i.c.v. had no effect on transit at any dose. When given peripherally, morphine, PLO17, DPDPE and U50,488H all inhibited diarrhea in a dose-related fashion. All four compounds inhibited diarrhea at doses much below those needed to cause analgesia. Morphine s.c. and PLO17 s.c. both inhibited diarrhea at doses lower than those required to inhibit transit. DPDPE s.c. and U50,488H s.c. had no effect on transit at any dose. The antidiarrheal effects of i.c.v. morphine, i.c.v. PLO17 and i.c.v. DPDPE were antagonized by pretreatment with 1 μg i.c.v. of naltrexone. Likewise, the antidiarrheal actions of s.c. PLO17, s.c. DPDPE and s.c. U50,488H were all blocked by 1 mg/kg s.c. of naltrexone. These findings indicate that supraspinal mu and delta, and peripheral mu, delta and kappa opioid receptors all possess antidiarrheal activity. Each compound prevented diarrhea without slowing the rate of transit, indicating an antisecretory-related mechanism of antidiarrheal action.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jan 1 1989


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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