Mice were rendered physically dependent by repeated administration of
morphine, 25 mg/kg s.c., 5 times daily for 4 days, and on the 5th day, 2 h after the last
morphine dose, they were challenged with a s.c. injection of either
naloxone, 25 mg/kg, or the peripherally selective
opioid antagonist SR 58002 C (N-methyl
levallorphan mesilate), 75 mg/kg.
Naloxone provoked jumping and
diarrhea in all the animals; mice challenged with
SR 58002 C presented no significant jumping but a high frequency of withdrawal
diarrhea. When
naloxone, 12 mg/kg, or
SR 58002 C, 50 mg/kg, were given s.c. in combination with repeated
morphine as above, mice which had received
naloxone with
morphine presented virtually no
diarrhea or jumping upon
naloxone challenge; those repeatedly treated with
morphine plus
SR 58002 C were substantially protected from
naloxone-precipitated
diarrhea, but not jumping. These results further support the remarkable selectivity for peripheral
opioid receptors of
SR 58002 C, even after repeated high-dose treatment, and are strongly consistent with the primary role of a local intestinal mechanism in the development and expression of
opioid withdrawal
diarrhea in mice. The in vivo dissociation of central and peripheral components of dependence on
morphine is illustrated, apparently for the first time.