Bone cancer pain is a major clinical problem and remains difficult to treat. ATP-sensitive potassium (K-ATP) channels may be involved in regulating nociceptive transmission at the spinal cord level. We determined the role of spinal K-ATP channels in the control of mechanical hypersensitivity in a rat model of bone cancer pain. The rat model of bone cancer pain was induced by implanting rat mammary gland carcinoma cells (Walker256) into the tibias. K-ATP modulators (pinacidil and glibenclamide) or the specific Kir6.2-siRNA were injected via an intrathecal catheter. The mechanical withdrawal threshold of rats was tested using von Frey filaments. The Kir6.2 mRNA and protein levels were measured by quantitative PCR and western blots, respectively. Intrathecal injection of pinacidil, a KATP channel opener, significantly increased the tactile withdrawal threshold of cancer cell-injected rats in a dose-dependent manner. In contrast, intrathecal delivery of glibenclamide, a K-ATP channel blocker, or the specific Kir6.2-siRNA significantly reduced the tactile withdrawal threshold of cancer cell-injected rats. The mRNA and protein levels of Kir6.2 in the spinal cord of cancer cell-injected rats were significantly lower than those in control rats. Our findings suggest that the K-ATP channel expression level in the spinal cord is reduced in bone cancer pain. Activation of K-ATP channels at the spinal level reduces pain hypersensitivity associated with bone cancer pain. (c) 2014 Elsevier B.V. All rights reserved.