BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, is reported to have an antinociceptive effect by hyperpolarization through the K ϩ channel. The activation of extracellular signal-regulated kinase (ERK), a family of mitogen-activated protein kinases, plays an important role in synaptic plasticity and noxious stimulation in the dorsal root ganglion, and spinal neurons have been reported to induce its activation. To understand the biological mechanisms of

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... andil, we examined the effects of nicorandil on muscarinic acetylcholine (ACh) receptor-mediated activation of ERK in a neuronal model cell, rat pheochromocytoma PC12 cells. METHODS: PC12 cells were stimulated with ACh in the presence or absence of nicorandil, and phosphorylation of ERK was examined by a Western blot analysis. We also examined the effects of nicorandil on the ERK activation induced by 4␤-phorbol 12-myristate 13-acetate, an activator of protein kinase C, or ionomycin, a calcium ionophore. Intracellular Ca 2ϩ increase was visualized in fluo-3-loaded PC12 cells using fluorescence microscopy. RESULTS: Nicorandil inhibited ACh-induced ERK activation in a concentrationdependent manner. The inhibition was abolished by glibenclamide, an adenosine triphosphate-sensitive potassium channel blocker. Nicorandil suppressed the ERK activation induced by ionomycin but not 4␤-phorbol 12-myristate 13-acetate. Pretreatment of PC12 cells with nicorandil reduced the intracellular Ca 2ϩ concentration stimulated by ACh. CONCLUSIONS: Nicorandil inhibits muscarinic activation of the ERK signaling pathway by reducing the intracellular Ca 2ϩ concentration.