Differential effects of general anesthetics on anxiety-like behavior in formalin-induced pain: involvement of ERK activation in the anterior cingulate cortex

Pain-related anxiety and depression are well known to be comorbid with chronic pain and adversely affect patient quality of life. Recent studies have shown that anxiety-like behaviors also develop with acute surgical pain, but the effects of general anesthetics on acute pain-related anxiety are unknown. The present study aimed to compare the effects of different general anesthetics on anxiety-like behaviors that follow formalin-induced acute pain in a rat model. Formalin-induced acute inflammatory pain was established by intraplantar injection of 1 % formalin without anesthesia or with anesthesia using the clinical anesthetics sevoflurane, propofol, or pentobarbital sodium. Anxiety-like behaviors were studied using the open-field test and elevated plus maze. Phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 expression in the anterior cingulate cortex (ACC) and spinal cord was examined using immunohistochemistry. Anxiety-like behaviors were observed at 24 and 72 h post-formalin injection. Concomitantly, p-ERK 1/2 expression was upregulated in the ACC at 1 and 24 h post-formalin injection. While all three general anesthetics effectively blocked nociceptive responses and activation of ERK in the rat ACC following formalin injection during anesthesia, only sevoflurane inhibited ERK activation in the spinal cord and ACC at 24 h post-injection. This study suggests that sevoflurane, but not intravenous anesthetics, inhibits pain-related anxiety, along with ERK activation in the ACC, probably through inhibition of spinal nociceptive transmission. Intraoperative application of inhaled anesthetics may be a better choice to reduce postoperative anxiety.