Central and peripheral sites of opioid action on net basal fluid transport were studied in loops of jejunum in urethane-anesthetized mice. Intracerebroventricular administration of morphine [D-Ala2, N-MePhe4, Gly-o]enkephalin (DAMGO), D-Pen2, D-Pen5]enkephalin (DPDPE) or U50,488H produced dose-related increases in net basal intestinal absorption. Intracerebroventricular DAMGO was approximately 2.6, 1278 and 2674 times more potent than morphine, DPDPE and U50,488H, respectively. The increase in net basal fluid absorption mediated by i.c.v. administration of all these compounds, except DPDPE, was antagonized in a dose-related manner by coadministration of i.c.v. naloxone, an opioid antagonist which did not produce any effects when given alone. Neither the increase in net basal fluid absorption produced by DPDPE nor the fluid transport effects produced by the other agonists tested was antagonized by the delta antagonist, N,N-diallyl-Tyr-α-aminoisobutyric acid ([Aib]-Aib-Phe-Leu-OH) and no effects were observed with this delta antagonist alone. Intracerebroventricular administration of β-funaltrexamine (18.8 nmol, 4 hr before testing) blocked the i.c.v. effects of DAMGO, but not those of U50,488H. In contrast to the effects seen following i.c.v. administration of these agonists, no changes in net basal fluid transport were obtained by the i.p. route for DAMGO, DPDPE, [D-Ala2,D-Leu5]enkephalin, [D-Ala2, Met5]enkephalinamide or U50,488H; of the compounds tested, only morphine produced an increase in net basal fluid absorption after i.p. administration. The effects of i.c.v. or i.p. morphine were blocked by i.c.v. SR 58002C, a quaternary opioid antagonist which had no effects alone. In contrast, the fluid transport effects of i.p. morphine were not blocked by i.p. SR 58002C, suggesting that morphine must enter the central nervous system to produce these actions. Intraperitoneal morphine also produced an inhibition of intestinal propulsion which was blocked in a dose-related manner by i.p. SR 58002C. Further, at the same i.p. doses, DAMGO or [D-Ala2, D-Leu5]enkephalin produced dose-related decreases in propulsion, without affecting net basal fluid transport. Finally, the effects of the i.c.v DAMGO and U50,488H were antagonized by i.c.v., but not i.p., SR 58002C. Collectively, these results suggest opioids enhance net basal fluid absorption by actions at central rather than intestinal sites in the mouse, and thus implicate both central opioid mu and kappa receptors in this effect. The centrally originating outflow pathways regulating fluid transport do not appear to involve endogenous opioids in the periphery. In contrast to effects on fluid transport, opioids can initiate changes in motility by actions at both central and peripheral sites. Thus, the data suggest that peripherally given opioids that do not penetrate the central nervous system may be producing their antidiarrheal effects mainly by altering motility, whereas opioids that enter the central nervous system may affect both motility and basal fluid transport.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1990|
ASJC Scopus subject areas
- Molecular Medicine