Loss of ATP-Sensitive Potassium Channel Expression and Function in the Nervous System Decreases Opioid Sensitivity in a High-Fat Diet–Fed Mouse Model of Diet-Induced Obesity

During diabetes progression, β-cell dysfunction due to loss of potassium channels sensitive to ATP, known as K_ATP channels, occurs, contributing to hyperglycemia. The aim of this study was to investigate if K_ATP channel expression or activity in the nervous system was altered in a high-fat diet (HFD)–fed mouse model of diet-induced obesity. Expression of two K_ATP channel subunits, Kcnj11 (Kir6.2) and Abcc8 (SUR1), were decreased in the peripheral and central nervous system of mice fed HFD, which was significantly correlated with mechanical paw-withdrawal thresholds. HFD mice had decreased antinociception to systemic morphine compared with control diet (CON) mice, which was expected because K_ATP channels are downstream targets of opioid receptors. Mechanical hypersensitivity in HFD mice was exacerbated after systemic treatment with glyburide or nateglinide, K_ATP channel antagonists clinically used to control blood glucose levels. Upregulation of SUR1 and Kir6.2, through an adenovirus delivered intrathecally, increased morphine antinociception in HFD mice. These data present a potential link between K_ATP channel function and neuropathy during early stages of diabetes. There is a need for increased knowledge of how diabetes affects structural and molecular changes in the nervous system, including ion channels, to lead to the progression of chronic pain and sensory issues.