Abstract

Meptazinol is a unique centrally active opioid analgesic, differing in many respects from the classical opiates or mixed antagonists. Although the overall binding of a series of 3H-labeled opioids is displaced poorly (IC50 values greater than 55 nM), detailed competition studies show that meptazinol inhibits a portion of 3H-labeled opiate and opioid peptide binding quite potently, with IC50 value under 1 nM. Both additional competition studies and saturation studies indicate that the meptazinol-sensitive binding of the 3H-ligands corresponds to the high affinity, or mu-1, binding site. In other binding studies meptazinol has a sodium shift of 8.7, midway between that of morphine (22.5) and naloxone (1.6), suggesting that it is a partial agonist. Naloxonazine treatment 24 hr earlier attenuates meptazinol analgesia in both the mouse writhing and rat tail-flick assays. Spinal transection in the mouse completely eliminates the analgesic activity of high doses of meptazinol in the tail-flick assay, implying a supraspinal mechanism of action in that species. Given at equianalgesic doses, morphine (3.5 mg/kg i.v.) significantly lowers the pO2 over 20 mm Hg and raises the pCO2 over 10 mm Hg as measured in arterial blood samples, whereas meptazinol (10 mg/kg i.v.) has no significant effects on either. Equally important, meptazinol administered with morphine does not reverse the respiratory depressant actions seen with morphine alone, distinguishing meptazinol from other mixed agonist/antagonists. Thus, both the binding and in vivo pharmacological studies are consistent with a mu-1 selective mechanism for the opioid actions of meptazinol.