[Physical dependence liabilities of butorphanol, a narcotic antagonist, and its main metabolites, norbutorphanol and hydroxybutorphanol].

After the intravenous injection of butorphanol or norbutorphanol in rats every 1 hr for 3 days, naloxone-induced body weight loss and withdrawal syndrome were observed to some degree. A slow-released emulsion containing each of the test drugs was injected subcutaneously in guinea-pigs, and naloxone was administered after 2 or 3 days. BT caused little jumping response even at a dose of 600 mg/kg, and the reaction was significantly weaker than that of pentazocine. No jumping responses were recognized in the cases of NB (600 mg/kg). In morphinized rats, the injection of BT or HB caused potent body weight loss, and these rats exhibited withdrawal syndrome which was more potent than that by pentazocine at the same dose. The body weight losses by the injection of NB and pentazocine were to the same degree, and these changes were significantly different from that of the saline control. BT inhibited the adenylate cyclase activity of the rat caudate nuclei, and the effect was weaker than that of pentazocine. NB showed a slight inhibition, and HB had no effect on the activity. These results suggest that the physical dependence liability of butorphanol is less than that of pentazocine, and the potent mu-antagonistic character of butorphanol is based on the liability. NB, a mu-agonist, makes dependence production possible. The ability of HB is negligible.