Signals for increase of μ-opioid receptor expression in muscle by hyperglycemia

Increase of μ-opioid receptor (MOR) expression in liver of diabetic rats has been mentioned to associate with hyperglycemia that can activate the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, STAT3 may regulate the expression of MOR genes. In the present study, role of STAT3 in the regulation of increased MOR expression was investigated in diabetic rats and cultured rat skeletal myoblast (L6) cells. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to estimate the response to MOR agonist (loperamide) and the changes in MOR expression. Then, cultured L6 cells incubated in high glucose (HG) medium were used to mimic the in vivo changes. Loperamide-induced hypoglycemia was more pronounced in STZ rats. The increased MOR expression in skeletal muscle of STZ rats was reversed by the reduction of hyperglycemia. Increased MOR expression and the enhanced expression of STAT3 observed in HG-exposed cultured L6 cells. Treatment with siRNA specific to STAT3 reversed the increased expression of MOR in this cell model. Treatment with stattic at a dose sufficient to inhibit STAT3 reversed MOR expression in STZ rats. We identified that hyperglycemia induces a greater expression of STAT3 to result in the increased expression of MOR, both in vivo and in vitro.