The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

Kappa opioid receptor (KOR) agonists like salvinorin-A produce psychotomimetic effects through largely unknown mechanisms. In a double-blind, crossover, randomized, placebo-controlled study, acute administration of salvinorin-A increased delta and gamma brain waves while decreasing alpha waves, as measured by electroencephalography. Single-photon emission computed tomography revealed significant decreases in regional cerebral blood flow across frontal, temporal, parietal, and occipital cortices, with increases in the medial temporal lobe, amygdala, hippocampal gyrus, and cerebellum. Subjective effects resembled other psychotomimetic drugs but were distinctly dissociative, with no dysphoria reported. KOR agonism by salvinorin-A induces dramatic psychotomimetic effects alongside generalized reductions in cortical blood flow and electrical activity.

Study at a glance

Abstract

The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist. Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design. The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported. The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.