Metabolic Changes in the Rodent Brain after Acute Administration of Salvinorin A

Abstract

Purpose-Salvinorin A (SA) is a potent and highly selective kappa opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined.Procedures-Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 18 FDG, followed by image acquisition in a dedicated animal PET system. Age-matched control animals received vehicle treatment. Animal behavior during 18 FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional 18 FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis.Results-SA treated animals demonstrated significant increases in 18 FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerbellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during 18 FDG uptake.Conclusions-We have provided the first extensive maps of cerebral metabolic activation due to the potent κ-opioid agonist, salvinorin A. A major finding from our small animal PET studies using 18 FDG was that neural circuits affected by SA may not be limited to direct activation or inhibition of kappa receptor-expressing cells. Instead, salvinorin A may trigger brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output. Significance: Salvinorin A is the major psychoactive compound from Salvia divinorum and is a potent kappa-opioid receptor agonist. Owing to its hallucinogenic properties, abuse liability, and medicinal potential as a kappa-agonist there has been a growing effort to characterize its physiological effects in rodents. Our manuscript describes our efforts to further inform how salvinorin A leads to behavioral (and physiological) changes in rodents. We have determined the regional differences (relative to controls) in glucose utilization in the brains of freely behaving rats after acute administration of salvinorin A. Using 18 FDG, we have mapped brain regions that are activated or deactivated as a result of the kappa agonist. We feel there will be an increasing need to systematically understand how affinity, pharmacokinetics, and distribution influence behavior through regional changes in brain activation. Our studies highlight the potential of 18 FDG with small animal PET to accomplish this. NIH Public Access

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…EOM Sal B and MOM Sal B have increased binding to KOPr compared to Sal A (Munro, Duncan, Xu, Wang, Liu-Chen, Carlezon et al, 2008) and MOM Sal B has been shown to be longer acting in vivo than Sal A in hotplate and hypothermic assays in the rat (Wang 2009). In a study by Hooker (2009) EOM Sal B gave 3 fold higher levels in the brain 65 min following ip. injection, indicating slower metabolism.…”

“…Both MOM Sal B and EOM Sal B have been shown to have a longer half-life in vivo compared to Sal A (Baker et al, 2009; Wang, Chen, Xu, Lee, Ma, Rawls et al, 2008). Hooker et al (2009) compared EOM Sal B to the parent compound, Sal A and showed that EOM Sal B had increased metabolic stability and decreased plasma protein affinity are likely mechanisms for its increased duration of effects (Hooker, Patel, Kothari, & Schiffer, 2009). …”

Why Do Plants Contain Biologically Active Compounds?

“…It was found that administration of the opioid antagonist naloxone neither reduced the concentration of [ 11 C]salvinorin A nor changed its distribution in the brain. Moreover, the metabolism of labeled salvinorin A occurred not only in the parts of the brain with high KOR density, but also in brain regions with little or no KOR presence (Hooker et al 2009). There is still a need for further studies to fully understand the mechanism of action of salvinorin A.…”

Statistical parametric maps of 18F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study

“…The size of the clusters exceeding the threshold and their corrected significance were evaluated and anatomically located using a ROI template [27] in Paxinos stereotaxic space.…”

“…The statistical threshold was set at p<0.005 with an extent threshold of 100 contiguous voxels. Activated clusters were evaluated and anatomically located using a ROI template [27].…”