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During diabetes progression, β-cell dysfunction due to loss of potassium channels sensitive to ATP, known as KATP channels, occurs, contributing to hyperglycemia. The aim of this study was to investigate if KATP 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 KATP 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 KATP channels are downstream targets of opioid receptors. Mechanical hypersensitivity in HFD mice was exacerbated after systemic treatment with glyburide or nateglinide, KATP 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 KATP 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., (© 2024 by the American Diabetes Association.)