Pain hypersensitivity and increased urinary tetrahydrobiopterin levels in mice submitted to high fat diet

Objective: This study aimed to examine the impact of high-fat diet (HFD)-induced obesity on pain sensitivity and tetrahydrobiopterin (BH4) levels. The effect of moderate-intensity physical exercise, an anti-inflammatory non-pharmacological intervention, on pain scores was also investigated. Methods: Adult male C57BL/J6 mice were fed standard or HFD for eight weeks. Total body weight, food intake, locomotor and motivational behavior and pain reflexes were measured. A subgroup of animals underwent physical exercise for five days per week over six weeks. Blood was collected for glucose tolerance testing and levels of lactate. Urine samples were collected to measure BH4 levels. Results: We showed that HFD increased weight gain, visceral white adipose tissue, and the percentage of body fat. These anthropometric alterations were characterized by impaired glucose tolerance at four and eight weeks of the dietary intervention. It was also observed reduced locomotor activity and higher pain scores in HFD-fed mice that were prevented by the physical exercise intervention. HFD also induced the increase of urinary BH4 levels at four and eight weeks of intervention. Conclusion: Urinary BH4 can be proposed as a potential easy-to-access, sensitive and reliable biomarker of pain development, and a promising target for the control of pain hypersensitivity in obesity.