SRC KINASE PLAYS A SEXUALLY DIMORPHIC ROLE IN THE MECHANISM UNDERLYING INTERMITTENT FASTING ENHANCED OPIOID ANTINOCICEPTION

Abstract

With its variety of positive reported effects, intermittent fasting was previously hypothesized to decrease negative outcomes associated with opioids. Ultimately, intermittent fasting combined with opioid therapy was shown to increase the antinociceptive effect of the opioids while decreasing the negative side effects, including abuse liability (1). In this study we thus attempted to elucidate the mechanism behind this enhancement of opioid antinociception by intermittent fasting. Proteomics was first performed in the spinal cord and significant differences in Src inhibitor 1 (Srcin1) was found between fasted and ad libitum mice, suggesting a role for Src kinase in this pathway. Western blotting was conducted, the results of which confirmed that in spinal cords Src kinase phosphorylation was increased by intermittent fasting. Next, Src inhibitor was administered to opioid treated fasted mice, which showed that enhanced opioid antinociception was abolished in male mice but not females. This sexually dimorphic effect was supported by immunohistochemistry, which showed that only in intermittent fasted opioid stimulated male mice, Src phosphorylation was greatly increased in the dorsal horn. Finally, colocalization was performed, though these results are preliminary, and no significant results have currently been found. Ultimately, these results suggest that decreased Srcin1 levels cause an increase in Src phosphorylation, regardless of sex, following intermittent fasting. Following opioid treatment, the dorsal horn of intermittent fasting male mice has increased Src phosphorylation that mediates enhanced antinociception. This has uncovered a role for Src kinase in intermittent fasting and opioid antinociception, as well as sexual dimorphism seen in both.