Adsorption and Conduction-Block of Opiate Narcotics on Nerve Membranes: Identical Effects of Levo- and Dextro-Forms

Abstract

(1) In order to detect the possible existence of stereospecific binding sites for the opiate narcotics, the adsorption and conduction-blocking action of the enantiomers of methadone and levorphanol were tested on nerve membranes.(2) The adsorption of radioactive dextro- and levo-methadone to homogenates of guinea pig brains were identical. The addition of nonradioactive levo-methadone displaced equal amounts of the radioactive dextro- and levo-methadones.(3) Simultaneous adsorption of 3H-levo-methadone and 14C-dextro-methadone to homogenates of various brain regions also did not reveal any stereoselective adsorption of the levo-isomer.(4) In vivo perfusion of guinea pig brain with 3H-levo-methadone simultaneously with 14C-dextro-methadone did not reveal any methadone uptake which was stereoselective for the levo-isomer and which was significantly different from skeletal muscle. In vivo perfusion with 3H-dextro-methadone simultaneously with 14C-levo-methadone also did not reveal stereoselectivity for the levo-form.(5) The synaptosome membrane/buffer partition coefficients for dextro- and levo-methadone were identical, having a value of 300 at 22°, and about 430 at 37° (in 10 mM sodium phosphate, pH 7). In 0.9% NaCl, the methadone partition coefficient fell to 32 (at 22 °C). The adsorption isotherm indicated only one set of binding sites.(6) The minimum concentrations required to block impulse conduction in rat phrenic nerve were 9.5 × 10−6 M for both dextro- and levo-methadone, 2 × 10−4 M for levorphanol, and 3 × to 4 × 10−4 M for dextrorphan.(7) It is possible that the binding is not stereospecific but that it is only the efficacy on the receptor which is stereospecific.