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
The male uro-genital tract is susceptible to gram-negative bacterial infections that produce a state of inflammation, particularly in the testis and epididymis. Development of germline stem cells into motile spermatozoa takes place in these organs and thus any impairment therein has a direct effect on male fertility. A number of factors are known to impair male fertility including environmental and chemical factors, lifestyle, and infections. The last is a little-known and poorly understood cause of male sub-/infertility. The presence of the pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF- alpha), interleukin-1alpha (IL-1alpha) and interleukin-1beta (IL-1beta) in the male uro-genital tract following bacterial infections suggests that such infections could have cytokine-mediated anti-fertility effects. Furthermore, inflammation has been associated with elevated levels of reactive oxygen species and oxidative stress both of which affect male fertility. The present article summarizes the effects of inflammation on the testis, epididymis and spermatozoa. We review the correlations between inflammation and oxidative stress vis-à-vis spermatogenesis and discuss the implications of infections on male fertility/infertility and assisted reproductive technologies for the male.
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