The psychotomimetic effects of opiates and the sigma receptor

Abstract

A critical review of the literature shows that the dysphoric and psychotomimetic side effects of sigma opiates reside in the levorotatory and not in the dextrorotatory or (+)-isomer, as currently believed. Nalorphine, levallorphan, (-)-pentazocine, (-)-3-hydroxy-N-propargylmorphinan, and MR 2034, all levorotatory opiates, produce dysphoria and psychotomimetic effects, whereas the dextrorotatory isomers of pentazocine and MR 2034 do not. Moreover, the dysphoria and psychotomimetic effects produced by racemic cyclazocine and MR 2034 are antagonized dramatically by naloxone, which is levorotatory and has no affinity for the sigma receptor as currently defined. The findings reviewed demonstrate that the psychotomimetic effects of sigma opiates are mediated by opiate receptors, the type of which has not been determined. The haloperidol sensitive sigma receptor, with higher affinity for the dextrorotatory isomers than for the sigma opiates, cannot mediate the psychotomimetic effects produced by levorotatory opiates. The conclusions derived from this review have profound implications, because a putative psychotomimetic receptor with the wrong stereospecificity will mislead future research, frustrate investigators, and confound the granting agencies.