Sex differences in the kynurenine pathway in chronic pain and depression comorbidity: clinical and preclinical studies

Abstract

Pain and depression are frequently comorbid disorders, and both are more prevalent in women than men, but the underlying mechanisms are unclear. Research suggests a link between kynurenine (KYN) metabolism and the development of pain and depression, due to the negative effects of central KYN metabolism. We hypothesize that neuropathic pain activates this pathway promoting anxiety and/or depression. We conducted a clinical study with healthy subjects and neuropathic pain patients, subdivided into two subgroups: neuropathic pain (DN4>4) and neuropathic painwith signs of moderate to high depression (DN4>4, HRSD21 ≥ 17). Plasma tryptophan (TRP) and KYN levels were evaluated using ELISA. Additionally, we used a murine model of chronic neuropathic pain (CCI) to evaluate sensory response and anxious-depressive-like behavior in both sexes. TRP and KYN levels in plasma and prefrontal cortex were evaluated using ELISA. We found higher DN4 scores in women than in men, with no sex differences in the comorbidity group. Plasma TRP levels were similar across groups, while KYN levels significantly decreased in women with neuropathic pain. In the preclinical study, all animals subjected to pain exhibited hypersensitivity to mechanical stimuli, while females also showed higher anxious-depressive-like behavior. Plasma TRP and KYN levels were higher in female mice at baseline, with a slight reduction inboth sexes after CCI induction. CCI groups showed a significant increase of KYN levels in prefrontal cortex, with a greater increase in females. The decrease in plasma KYN levels in both, neuropathic pain patients and mice, together with the increase in central KYN levels, mainly in female mice, suggests a greater balance of KYN input at the central level, accompanied by the onset of anxiety and/or depressive-like behaviors. Thus, KYN pathway may play a relevant role in the vulnerability to anxiety and depression observed in women.