Cingulate GABA levels inversely correlate with the intensity of ongoing chronic knee osteoarthritis pain

Background: This study aims to investigate the role of the mid-anterior cingulate cortex gamma-aminobutyric acid levels in chronic nociceptive pain. The molecular mechanisms of pain chronification are not well understood. In fibromyalgia, low mid-anterior cingulate cortex gamma-aminobutyric acid was associated with high pain suggesting a role of prefrontal disinhibition. We hypothesize that mid-anterior cingulate cortex GABAergic disinhibition may underpin chronic pain independent of the pain etiology and comorbid negative affect. Proton magnetic resonance spectra were acquired at 3T from the mid-anterior cingulate cortex in 20 patients with chronic painful knee osteoarthritis, and 19 healthy pain-free individuals using a point resolved spectroscopy sequence optimized for detection of gamma-aminobutyric acid. Participants underwent questionnaires for negative affect (depression and anxiety) and psychophysical pain phenotyping. Results: No differences in mid-anterior cingulate cortex gamma-aminobutyric acid or other metabolite levels were detected between groups. Ratings of perceived intensity of ongoing osteoarthritis pain were inversely correlated with gamma-aminobutyric acid (r = -0.758, p<0.001), but no correlations were seen for negative affect or pain thresholds. The pain gamma-aminobutyric acid interrelation remained strong when controlling for depression (r = -0.820, p<0.001). Combined levels of glutamine and glutamate were unrelated to psychometric or to pain thresholds. Conclusion: Our study supports mid-anterior cingulate cortex gamma-aminobutyric acid as a potential marker of pain severity in chronic nociceptive pain states independent of negative affect. The findings suggest that GABAergic disinhibition of the salience network may underlie sensitization to averse stimuli as a mechanism contributing to pain chronification.