The kappa opioid receptor and the sleep of reason: Cortico-subcortical imbalance following salvinorin-A
Acute administration of salvinorin-A, a highly selective kappa opioid receptor agonist, produced dramatic dissociative psychotomimetic effects without dysphoria and revealed a cortico–subcortical imbalance. Neurophysiologically this was reflected by widespread cortical hypoperfusion and reduced cortical EEG alpha (with increased delta and gamma) alongside increased blood flow in medial temporal regions (amygdala, hippocampal gyrus) and the cerebellum.
Authors
- Jordi Riba
- Gonzalo Ona
- Marta Valle
Published
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Research Summary of 'The kappa opioid receptor and the sleep of reason: Cortico-subcortical imbalance following salvinorin-A'
Introduction
Opioid receptors (µ, δ, and κ) were identified in the 1970s and differ in distribution, ligand selectivity, and behavioural effects. Whereas µ opioid receptor agonists produce potent analgesia accompanied by euphoria and addiction risk, kappa opioid receptor (KOR) agonists have shown analgesic, antidepressant, and neuroprotective properties but are often associated with dysphoria and psychotomimetic effects. The mechanisms that underlie KOR-induced dysphoria and the hallucinatory or psychotomimetic phenomena remain unclear. Early human investigations of KOR agonists have reported vivid alterations of perception, depersonalisation, and disturbances of space and time; together these observations suggest that KOR agonism may produce a pattern of subjective and neurophysiological effects that differs from classical serotonergic psychedelics mediated by 5-HT2A receptors. Ona and colleagues set out to characterise the functional brain changes produced by full KOR agonism using salvinorin-A, a highly selective non‑nitrogenous KOR agonist. Because salvinorin-A has a very rapid onset and brief peak effect, the investigators combined two complementary sub-studies: an EEG study (sub-study 1) to capture rapid electrophysiological dynamics, and a SPECT study (sub-study 2) to capture regional cerebral blood flow (rCBF) at the drug's peak while also collecting subjective measures. The overarching aim was to link subjective phenomenology with electrophysiological and perfusion signatures of KOR activation in healthy volunteers with prior hallucinogen experience.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Ona, G., Sampedro, F., Romero, S., Valle, M., Camacho, V., Migliorelli, C., Mañanas, M. Á., Antonijoan, R. M., Puntes, M., Coimbra, J., Ballester, M. R., Garrido, M., & Riba, J. (2022). The kappa opioid receptor and the sleep of reason: Cortico-subcortical imbalance following salvinorin-A. International Journal of Neuropsychopharmacology, 25(1), 54-63. https://doi.org/10.1093/ijnp/pyab063
References (14)
Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Roseman, L., Bolstridge, M. et al. · Scientific Reports (2017)
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
De Araujo, D. B., Ribeiro, S., Cecchi, G. A. et al. · Human Brain Mapping (2011)
Doss, M. K., May, D. G., Johnson, M. W. et al. · Scientific Reports (2020)
Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A. et al. · Pharmacopsychiatry (2005)
Kraehenmann, R., Preller, K. H., Scheidegger, M. et al. · Biological Psychiatry (2015)
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R. et al. · Trends in Pharmacological Sciences (2017)
Maqueda, A. E., Valle, M., Addy, P. H. et al. · International Journal of Neuropsychopharmacology (2015)
Mueller, F., Lenz, C., Dolder, P. C. et al. · Translational Psychiatry (2017)
Show all 14 referencesShow fewer
Müller, F., Dolder, P. C., Schmidt, A. et al. · NeuroImage (2018)
Palhano-Fontes, F., Andrade, K. C., Tófoli, L.F. et al. · PLOS ONE (2015)
Riba, J., Valle, M., Urbano, G. et al. · Journal of Pharmacology and Experimental Therapeutics (2003)
Timmermann, C., Roseman, L., Schartner, M. et al. · Scientific Reports (2019)
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