Tolerance to the Effect of Morphine on Intestinal Transit

Introduction. The repeated or “chronic” injection of a narcotic analgesic, exemplified by morphine, often results in the phenomena of tolerance and physical dependence (1-3). In regard to the gastrointestinal tract, however, the responses to repeated administration of morphine are not clear. Tolerance to the effects of morphine on intestinal contractions in vitro appears to develop. The isolated ileum of the guinea pig is inhibited by morphine and tolerance develops to this inhibition (4). Also, tolerance develops to morphine's stimulation of dog isolated small intestine (5). On the other hand, results on the development of tolerance to the intestinal actions of morphine in vivo are meager and conflicting. Miller and Plant monitored intraluminal pressures from the intestines of unanesthetized dogs and found that tolerance did not develop to the stimulatory effects of morphine (6). In contrast, Thor et al. monitored the myoelec-tric activity of the small bowel of the unanesthetized dog and found that tolerance did develop to the stimulant action of morphine (7). Motility functions of the small intestine can be investigated by following the transit of a nonabsorbable marker. Alterations in transit are believed to be secondary to changes in the contractile patterns of the small intestinal musculature. This study was designed to: (i) assess quantitatively whether acute injections of morphine affect intestinal transit in unanesthetized rats, and (ii) determine whether prior treatment of the rats with repeated injections of morphine produces tolerance to the observed effects. Materials and methods. Intraduodenal catheters were implanted in 32 Sprague-Dawley rats (Sprague-Dawley, Madison, Wis.) weighing 203 ± 4 g (mean ± SE). Details of implantation have been reported (8). Briefly, the animals were anesthetized with 20 mg of ketamine hydrochloride (Ke-taject, Bristol Laboratories, Syracuse, N.Y.) administered intraperitoneally.