No abstract

Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund’s adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10 days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.

Maternal stress has a profound impact on the long-term behavioral phenotype of offspring, including behavioral responses to stressful and social situations. In this study, we examined the effects of maternal exposure to predator odor, an ethologically relevant psychogenic stressor, on stress-induced behaviors in both semi-naturalistic and laboratory-based situations. Adult C57BL/6 mice offspring of dams exposed to predator odor during the last half of pregnancy showed increased anti-predatory behavior, more cautious foraging behavior and, in the elevated plus maze, avoidance of elevated open areas and elevated open areas following restraint stress challenge. These offspring also exhibited alterations in social behavior including reduced free interaction and increased initial investigation despite normal social recognition. These changes in behavior were associated with increased transcript abundance of corticotropin-releasing factor, mineralocorticoid receptor and oxytocin (Oxt) in the periventricular nucleus of the hypothalamus. Taken together, the findings are consistent with a long-term increase in ethologically-relevant behavioral and neural responses to stress in male and female offspring as a function of maternal predator odor exposure.