EVIDENCE FOR SIGMA-OPIOID RECEPTOR - BINDING OF [H-3]-LABELED SKF-10047 TO ETORPHINE-INACCESSIBLE SITES IN GUINEA-PIG BRAIN

Abstract

A portion of the specific binding of [3H]-SKF-10047 to the guinea pig brain suspension of the particulate fraction is not inhibited by the strong narcotic analgesic l-etorphine. The binding properties of these etorphine-inaccessible (El) sites were examined. The specific binding of [3H]SKF-10047 to the El sites is saturable. Scatchard analysis of the saturation curve revealed a single class of binding sites with apparent Kd of 252 nM and an estimated Bmax [maximum binding] of 663 fmol/mg protein. The El binding was reduced by heat treatment, trypsin digestion and phospholipase C digestion. The presence of Na+ slightly increased specific El binding. Li3+ increased the El binding by .apprx. 38% at the optimal concentration of 1 mM. Divalent cations such as Mg2+, Ca2+ and Mn2+ reduced El binding. Morphine-like drugs such as morphine, levorphanol and naltrexone were poor inhibitors for the El binding, whereas opioid derivatives such as pentazocine, dextrallorphan, cyclazocine, SKF-10047 and dextrorphan were potent inhibitors. Nonopioid drugs such as haloperidol, imipramine, pimozide and propranolol were also potent inhibitors of the El binding. Distribution of the El sites in brain was different from that of the .mu. receptor: highest concentration of El sites was found in brainstem, midbrain and cerebellum, whereas lower concentrations were found in striatum and cortex. El sites are apparently not .mu. receptors but may represent .sigma. receptors in the CNS, mediating psychotomimetic effects of several opioids and other drugs.