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Pain. 2015 May;156(5):849-58. doi: 10.1097/j.pain.0000000000000124.

In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model.

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aDepartment of Anesthesiology, Columbia University Medical Center, New York, NY, USA bDepartment of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.


N-methyl-D-aspartate receptor (NMDAR) antagonists have been shown to reduce mechanical hypersensitivity in animal models of inflammatory pain. However, their clinical use is associated with significant dose-limiting side effects. Small-conductance Ca-activated K channels (SK) have been shown to modulate NMDAR activity in the brain. We demonstrate that in vivo activation of SK channels in the spinal cord can alleviate mechanical hypersensitivity in a rat model of inflammatory pain. Intrathecal (i.t.) administration of the SK channel activator, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), attenuates complete Freund adjuvant (CFA)-induced mechanical hypersensitivity in a dose-dependent manner. Postsynaptic expression of the SK channel subunit, SK3, and apamin-sensitive SK channel-mediated currents recorded from superficial laminae are significantly reduced in the dorsal horn (DH) after CFA. Complete Freund adjuvant-induced decrease in SK-mediated currents can be reversed in vitro by bath application of NS309. In addition, immunostaining for the SK3 subunit indicates that SK3-containing channels within DH neurons can have both somatic and dendritic localization. Double immunostaining shows coexpression of SK3 and NMDAR subunit, NR1, compatible with functional interaction. Moreover, we demonstrate that i.t. coadministration of NS309 with an NMDAR antagonist reduces the dose of NMDAR antagonist, DL-2-amino-5-phosphonopentanoic acid (DL-AP5), required to produce antinociceptive effects in the CFA model. This reduction could attenuate the unwanted side effects associated with NMDAR antagonists, giving this combination potential clinical implications.

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