PT - JOURNAL ARTICLE AU - Yoshinori Hayashi AU - Kodai Kawaji AU - Li Sun AU - Xinwen Zhang AU - Kiyoshi Koyano AU - Takeshi Yokoyama AU - Shinichi Kohsaka AU - Kazuhide Inoue AU - Hiroshi Nakanishi TI - Microglial Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels Are Possible Molecular Targets for the Analgesic Effects of <em>S</em>-Ketamine on Neuropathic Pain AID - 10.1523/JNEUROSCI.4152-11.2011 DP - 2011 Nov 30 TA - The Journal of Neuroscience PG - 17370--17382 VI - 31 IP - 48 4099 - http://www.jneurosci.org/content/31/48/17370.short 4100 - http://www.jneurosci.org/content/31/48/17370.full SO - J. Neurosci.2011 Nov 30; 31 AB - Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca2+-activated K+ (KCa) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance KCa (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a KCa channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X4 receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.