Agonist and antagonist properties of buprenorphine, a new antinociceptive agent.

1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.