The analgesic effect of quaternary analogues of morphine and nalorphine.

1. The effects of N-methyl morphine and N-methyl nalorphine were studied on the hyperalgesia induced by prostaglandin E2 in the rat paw. Morphine and N-methyl morphine injected intraperitoneally (2-8 mg/kg) caused a dose-dependent analgesia. The potency of N-methyl morphine was of the same order of magnitude as its parent compound in causing analgesia. 2. Nalorphine caused a short-lasting analgesia followed by an enhancement of prostaglandin-induced hyperalgesia. In contrast, its analogue, N-methyl nalorphine, injected intraperitoneally, induced analgesia but did not enhance the hyperalgesia induced by prostaglandin E2 or induce hyperalgesia in the control paw. 3. Treatment of the animals with N-methyl nalorphine at a dose which had no apparent analgesic effect antagonized the analgesic effect of morphine or N-methyl morphine. 4. Administration of a low dose of N-methyl nalorphine into the paw totally antagonized the analgesic effect of N-methyl morphine administered either locally into the paw, or intraperitoneally. 5. It is concluded that quaternary analogues of morphine and nalorphine, which do not have central effects because they do not cross the blood-brain barrier, retain the peripheral analgesic effects of the parent compounds.