Gmerek D E, Cowan A, Woods J H
J Pharmacol Exp Ther. 1986 Jan;236(1):8-13.
The individual contributions of central (brain) and peripheral (enteric) sites in the mediation of the systemic actions of opioids are not well established. In this study, we made use of naltrexone methobromide, a quaternary analog of naltrexone, to separate the central and peripheral components of the slowing action of morphine on gastrointestinal transit in rats. It was established that i.c.v., but not s.c., administration of quaternary naltrexone antagonized morphine-induced analgesia in the radiant-heat tail-flick assay in rats. Thus, quaternary naltrexone probably does not enter the central nervous system in significant amounts after systemic administration. Systemic quaternary naltrexone antagonized, in a dose-related manner, the delaying effects of morphine on the movement of a charcoal meal along the gastrointestinal tract. Quaternary naltrexone was 30 or 100 times less potent than naltrexone when administered s.c. or i.c.v., respectively. Unlike naltrexone, quaternary naltrexone antagonized morphine-induced slowing of gastrointestinal transit only when administered by the same route (i.e., both s.c. or both i.c.v.). The apparent pA2 for s.c. quaternary naltrexone against s.c. morphine was not significantly different from the apparent pA2 for i.c.v. quaternary naltrexone against i.c.v. morphine. Distinct and independent central and peripheral systems appear to mediate morphine-induced inhibition of gastrointestinal transit in rats. However, the receptors are probably of the same type. Peripherally selective antagonists such as quaternary naltrexone may be useful in reversing morphine-induced inhibition of gastrointestinal transit without affecting analgesia.
