Studies to determine whether there is tolerance or cross-tolerance to the antisecretory effect of morphine and clonidine in the rat intestine.
Intra-arterial infusions (4 micrograms min-1) of prostaglandin E2 (PGE2) were used to stimulate intestinal fluid secretion in anaesthetized rats. Morphine (0.625-40 mg kg-1) produced a dose-dependent restoration of fluid transport from secretion to the normal rate of absorption. Pretreatment with up to eight doses of morphine (20 mg kg-1) did not induce tolerance, rather it enhanced the antisecretory effect of a subsequent acute dose of morphine. It seems probable that this was caused by the accumulation of morphine in the intestine. Clonidine (4-1000 micrograms kg-1, like morphine, produced a dose-dependent reversal of stimulated fluid secretion. Pretreatment with clonidine (4 x 0.25 mg kg-1) caused a shift of the clonidine antisecretory dose-response curve to the right, demonstrating tolerance. Pretreatment with clonidine also caused cross-tolerance to the antisecretory effect of morphine. The results suggest that there is a close relationship between opioid- and alpha 2-adrenoceptors in controlling inhibition of intestinal fluid secretion.
Unit of Addictive Drug Research, School of Pharmacology, Victorian College of Pharmacy, Parkville, Australia.
J
J
Margaritis
I M
IM
Coupar
G A
GA
Bentley
D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D051381:Rats
D009020:Morphine; D015232:Dinoprostone; D003000:Clonidine