Naloxonazine actions in vivo

Naloxonazine is a relatively selective μ₁ affinity label in binding studies. Like naloxazone, naloxonazine has proven valuable in vivo in establishing a role for μ₁ sites in specific opiate actions. We now report a detailed characterization of naloxonazine's actions in mice and rats. Naloxonazine antagonized morphine analgesia for greater than 24 h without altering lethality. This prolonged action could not be easily explained by a slow rate of elimination since the terminal elimination half-life was estimated at less than 3 h. Furthermore, these actions were associated with a wash-resistent inhibition of binding lasting 24 h which was relatively selective for μ₁ sites. At a fixed morphine dose, increasing naloxonazine doses lowered peak tailflick latencies in a biphasic manner, suggesting that morphine analgesia consisted of both μ₁ (naloxonazine-sensitive) and a non-μ₁ (naloxonazine-insensitive) components. The ratio of μ₁ to non-μ₁ analgesia was greater at low morphine doses, implying that morphine activated μ₁ analgesic mechanisms with higher affinity. Our studies also emphasized that naloxonazine has reversible actions similar to those of naloxone; only its irreversible actions are relatively μ₁-selective. In addition, the selectivity of naloxonazine's irreversible actions is dose-dependent. High naloxonazine doses will irreversibly antagonize receptors other than μ₁.