Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala

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.

The influence of the enriched environment in different periods on neonatal maternal separation-induced visceral pain, anxiousness, and depressive behaviors

“…Although we found no significant effect of EE intervention in early adulthood on NMS mice, which is inconsistent with some reports, we found a certain improvement trend in the experiment, which may be caused by the short duration of EE intervention, and extending the duration of EE intervention may also achieve positive effects. In addition, previously studies shown that elevating levels of corticosterone increases anxiety-and depressionlike behaviors, induces visceral hypersensitivity, and decreases somatic pain thresholds (20)(21)(22)(23)(24). Consistent with this, preadult EE tended to normalize plasma corticosterone levels in NMS mice, whereas adult EE had no positive effect on plasma corticosterone reduction, suggesting that corticosterone plays an important role of EE in the improvement of visceral pain, anxiety, and depressive behaviors induced by NMS.…”

General Anesthesia Activates a Central Anxiolytic Center in the BNST

“…We thus probed whether ChR2 activation of ovBNST GA neurons could also alleviate anxiety-like behaviors in an inflammatory pain model. We used an intraplantar injection of complete Freund’s adjuvant (CFA), which is known to induce long-lasting inflammatory pain and anxiety-like behavior in animals 36,37 . Indeed, activation of ovBNST GA neurons in the CFA model resulted in increased exploration to the OF center and EPM and EZM open arms compared to control CFA-injected mice.…”

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation

“…Therefore, in this study we focused on the effect of repeated intrathecal injections catalpol on the established pain behavior of CFA. In addition, previous studies have shown that chronic pain has the potential to increase the emergence of anxiety and produce symptoms of co-morbid anxiety in pain ( Shao et al, 2021 ; Farzinpour et al, 2022 ; Spinieli et al, 2022 ), so we investigated whether established persistent inflammatory pain induced by CFA can promote anxiety-like behavior in rats and whether catalpol alleviates after repeated treatment. This was confirmed by our results.…”