INVOLVEMENT OF THE MC4R PATHWAY IN THE DEVELOPMENT OF HYPERSENSITIVITY AND SEX-RELATED DIFFERENCES IN OBESE AND DIABETIC MICE

Diabetic and obese patients are prone to developing pain hypersensitivity due to their underlying conditions. The MC4 receptor (MC4R) is well known for its role in controlling food intake, but it has also been shown to modulate nociceptive processes, with its antagonists exhibiting analgesic effects. This study aimed to investigate the role of the MC4 receptor signaling pathway in the development of mechanical and thermal hypersensitivity in male and female mice with diabetes or obesity. The experiments were performed on male and female C57BL/6 naive, STZ-treated diabetic, and obese Lep^ob/ob mice. Pain-related behavior was assessed using the von Frey and cold plate tests. MC4R, POMC, AgRP, CREB, PKA, MAPK, JNK, ATF3 mRNA and protein levels were analyzed by qRT-PCR and Western blot, respectively. Our results show that by 15 weeks of age, Lep^ob/ob mice exhibit increased body weight accompanied by mechanical and thermal hypersensitivity. At the same time, two weeks after STZ treatment, diabetic mice show increased blood glucose level and mechanical and thermal hypersensitivity. Concurrently, MC4R expression and key components of its signaling pathway are altered, and sex-related differences are observed. Based on our findings, we suggest that the MC4R signaling pathway may play an important role in the pathophysiology of diabetic and obesity-induced hypersensitivity. This research was funded by the National Science Centre, Poland, grant SONATA 17 2021/43/D/NZ5/02559 and statutory funds from the Maj Institute of Pharmacology PAS.