Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up-regulation in vivo.

1. It has recently been suggested that opioid antagonists may be divided into those possessing negative intrinsic activity (e.g. naloxone) and those with neutral intrinsic activity (e.g. MR2266). 2. MR2266 was chronically administered to rats by subcutaneous infusion at a dose of 0.3 mg kg-1 h-1 for 1 week. 3. This dose reduced ingestive behaviour and blocked the antinociceptive effects of a kappa-agonist, indicating occupation of opioid receptors in vivo. 4. No supersensitivity could be detected to the antinociceptive actions of mu or kappa agonists, either one or two days after cessation of treatment. 5. No up-regulation of mu, delta or kappa binding sites was observed. 6. Since naloxone induces both supersensitivity and receptor up-regulation under equivalent conditions, the results suggest that negative intrinsic activity may be required for these phenomena to occur.