Microglial Ca 2+-activated K + channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain

Yoshinori Hayashi, Kodai Kawaji, Li Sun, Xinwen Zhang, Kiyoshi Koyano, Takeshi Yokoyama, Shinichi Kohsaka, Kazuhide Inoue, Hiroshi Nakanishi

Research output: Contribution to journalArticle

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Abstract

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 Ca 2+-activated K + (K Ca) currents in microglia, which areknownto induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K Ca (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 K Ca channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X 4 receptors, and the synthesis of brainderived 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.

Original languageEnglish
Pages (from-to)17370-17382
Number of pages13
JournalJournal of Neuroscience
Volume31
Issue number48
DOIs
Publication statusPublished - Nov 30 2011

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Ketamine
Neuralgia
Microglia
Analgesics
Hyperalgesia
N-Methyl-D-Aspartate Receptors
Wounds and Injuries
Large-Conductance Calcium-Activated Potassium Channels
Chronic Pain
Charybdotoxin
Nociceptors
Nerve Growth Factors
Acute Pain
Analgesia
Lipopolysaccharides
Adenosine Triphosphate

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Microglial Ca 2+-activated K + channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. / Hayashi, Yoshinori; Kawaji, Kodai; Sun, Li; Zhang, Xinwen; Koyano, Kiyoshi; Yokoyama, Takeshi; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi.

In: Journal of Neuroscience, Vol. 31, No. 48, 30.11.2011, p. 17370-17382.

Research output: Contribution to journalArticle

Hayashi, Yoshinori ; Kawaji, Kodai ; Sun, Li ; Zhang, Xinwen ; Koyano, Kiyoshi ; Yokoyama, Takeshi ; Kohsaka, Shinichi ; Inoue, Kazuhide ; Nakanishi, Hiroshi. / Microglial Ca 2+-activated K + channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 48. pp. 17370-17382.
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AU - Koyano, Kiyoshi

AU - Yokoyama, Takeshi

AU - Kohsaka, Shinichi

AU - Inoue, Kazuhide

AU - Nakanishi, Hiroshi

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