Naloxone-inaccessible sigma receptor in rat central nervous system.

It has been postulated that the psychotomimetic effects of opiates of the benzomorphan series are due to their activity at the sigma receptor. Therefore, the binding of (+/-)-[3H]ethylketocyclazocine ( [3H]EKC), a benzomorphan, to synaptosomal membranes of rat central nervous tissue was studied. Surprisingly, high concentrations of naloxone, a mu, delta, and kappa receptor antagonist, only inhibited about 80% of the specifically bound [3H]EKC in the spinal cord. This suggested that the remaining 20% of the binding sites were not mu, delta, or kappa. The Scatchard plot of the binding of [3H]EKC was nonlinear but became linear in the presence of naloxone (1 microM), suggesting a single class of naloxone-inaccessible receptor sites. This biochemically readily distinguishable receptor type bound the dextrorotatory isomer of EKC stereoselectively. The sigma agonist N-allylnormetazocine [(+)-SKF 10,047] stereoselectively competed with the binding of [3H]EKC to this naloxone-inaccessible binding site. A number of opiates that have psychotomimetic activity also competed for binding to this binding site. This binding site is designated as sigma binding site according to the nomenclature originally suggested by Martin et al. [Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E. & Gilbert, P. E. (1976) J. Pharmacol. Exp. Ther. 197, 517-532]. The drug selectivity and regional distribution of this sigma binding site in the rat central nervous system are different from that of the mu and delta opioid receptors and phencyclidine receptors. The concentration of the sigma binding site is highest in the spinal cord, pons and medulla, and cerebellum.