Stress Induces Prolonged Pain Recovery After Surgery: Involvement of Glucocorticoid-Related Pathway

Abstract

Background: Increasing evidence suggests that chronic stress increases pain sensitivity and exacerbates existing pain. However, whether and how chronic unpredictable stress (CUS) affects surgical pain is unclear.

Methods: A postsurgical pain model was performed by longitudinal incision from 0.3 cm of the proximal edge of the heel toward the toes. The skin was sutured, and the wound site was covered. Sham surgery groups underwent the same procedure without an incision. The short-term CUS procedure was conducted by exposure of mice to 2 different stressors each day for 7 days. The behavior tests were conducted between 9:00 am and 4:00 pm. Mice were killed on day 19, and the mouse bilateral L4/5 dorsal root ganglia, spinal cord, anterior cingulate and insular cortex, and amygdala were collected for immunoblot analyses.

Results: Presurgical exposure of mice to CUS every day for 1-7 days showed significant depression-like behavior as evidenced by reduced sucrose preference in the sucrose consumption test and prolonged immobility time in the forced swimming task. This short-term CUS procedure did not affect the basal nociceptive response to mechanical and cold stimuli in the Von Frey and acetone-induced allodynia tests, but it delayed pain recovery after surgery, as indicated by the prolonged hypersensitivity in mechanical and cold stimuli by 12 days. The subsequent studies demonstrated that this CUS caused an increase in adrenal gland index. The abnormalities in pain recovery and adrenal gland index after surgery were reversed by a glucocorticoid receptor (GR) antagonist RU38486. Moreover, the prolonged pain recovery after surgery induced by CUS seemed to involve an increase in GR expression and decreases in cyclic adenosine monophosphate, phosphorylated cAMP response element binding protein, and brain-derived neurotrophic factor levels in emotion-related brain regions, such as anterior cingulate and insular cortex, amygdala, dorsal horn, and dorsal root ganglion.

Conclusions: This finding indicates that stress-induced GR change may result in dysfunction of GR-related neuroprotective pathway.

Keywords: BDNF; Chronic unpredictable stress; cAMP; glucocorticoid receptor; pCREB; pain recovery.