The peripheral activity of the quaternary
narcotic antagonist N-methyl
levallorphan-methane sulphonate (
SR 58002 C) at
opioid sites located in the periphery and in the central nervous system (CNS), was studied by different approaches in rats after
subcutaneous injection (s.c.). Pretreatment with
SR 58002 C 2,8 or 32 mg/kg s.c. 10, 50 or 110 min before
buprenorphine consistently reduced
buprenorphine in vivo binding only in the small intestinal longitudinal muscle with attached myenteric plexus (MP), whereas
naloxone (1 mg/kg s.c.) 10 min before
buprenorphine lowered
buprenorphine binding in MP and brain (without cerebellum). Plasma levels were not altered by
SR 58002 C or
naloxone. The same doses of
SR 58002 C injected 10, 50 or 110 min before
morphine selectively antagonized the inhibition of transit of a
charcoal meal along the small intestine (mainly a peripheral effect) induced by the agonist, but did not antagonize
morphine-elicited
analgesia in the hot-plate test (central effect).
Naloxone (1 mg/kg s.c.) injected 10 min before
morphine antagonized both agonist effects simultaneously. In
morphine-dependent rats
SR 58002 C (0.25, 1, 4 and 32 mg/kg s.c.) induced
diarrhea, dose-dependently, in most animals within the first 30 min, while jumping, measured in the same rats, occurred in some animals, not dose-dependently, from 60 min on.
Naloxone (1 mg/kg s.c.) induced both effects in most rats. These findings suggest that, although
SR 58002 C probably penetrates the blood-brain barrier in some
morphine-dependent rats, it discriminates peripheral and CNS
opioid effects.