Spinally mediated opioid antidiarrheal effects.
To assess the role of opioid receptors in the spinal cord in regulation of functions of the intestinal mucosa in a secretory model, we evaluated the ability of i.t. administered mu (PL017), delta (DPDPE) and kappa (U50,488H) selective opioid agonists to inhibit diarrhea produced in mice by an injection of prostaglandin E2 (PGE2) (200 micrograms/mouse, i.p.). I.t. PL017 and DPDPE inhibited diarrhea in a dose-related fashion. U50,488H had only minimal antidiarrheal effects. The i.t. doses of PL017 and DPDPE required to inhibit diarrhea were higher than the doses required to produce antinociception and inhibit gastrointestinal transit. Spinally administered PL017 and DPDPE were considerably less potent in the diarrhea model than after i.c.v. administration but far more effective than after peripheral (s.c.) dosing. The antidiarrheal effects of spinally administered opioids were antagonized by concurrently administered naloxone. These data indicate that opioid chemosensitive sites in the spinal cord can modulate diarrhea produced by PGE2, and that the receptor specific opioids, PL017 and DPDPE, and to a lesser extent U50,488H, all possess antidiarrheal activity when administered i.t.
Lemcke
P K
PK
Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson 85724.
Shook
J E
JE
Burks
T F
TF
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000930:Antidiarrheals; D001835:Body Weight / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D015232:Dinoprostone; D004723:Endorphins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013116:Spinal Cord / Q000502:physiology*
D000700:Analgesics; D000930:Antidiarrheals; D004723:Endorphins; D004745:Enkephalins; D009294:Narcotics; D011759:Pyrrolidines; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D015232:Dinoprostone