Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives.

The effects of the pure narcotic antagonists, naloxone and naltrexone, and their quaternary derivatives, methylnaloxone and methylnaltrexone, were examined in reversing the catalepsy induced by morphine in rats. Morphine, 20 mg/kg, induced rigid catalepsy which attained a peak effect (as manifested by duration of catalepsy) at 60-120 min and progressively declined thereafter. Both naloxone and naltrexone, administered subcutaneously 40 min after the injection of morphine, dose-dependently reduced the duration of the catalepsy at doses of 10-30 micrograms/kg. Methylnaloxone also completely reversed the catalepsy at doses of 1-10 mg/kg, when given subcutaneously. In contrast, the subcutaneous administration of methylnaltrexone only partially reversed the catalepsy at doses up to 56 mg/kg 60-90 min post-morphine. The extent of the reversal of catalepsy produced by methylnaltrexone tended to increase with time. Methylnaltrexone, administered into the cerebral ventricles 70 min after the injection of morphine, completely suppressed the catalepsy with an ED50 of approx. 1 microgram/kg when tested at 90 min after morphine. These results indicate that opiate-induced catalepsy is predominantly mediated at sites within the central nervous system. Methylnaltrexone is about 10,000 times more potent in reversing catalepsy when administered centrally than when administered peripherally. Thus, methylnaltrexone may be useful in defining sites of opiate action and in therapeutically blocking undesirable peripheral effects of opiate analgesics.