BK channel in microglia as a potent therapeutic molecular target for neuropathic pain

Abstract

a b s t r a c tBackground: Ketamine, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been used in the treatment of chronic neuropathic pain. However, serious troubles have still remained in ketamine for the clinical treatment because of the strong adverse side effects during the long-term use. S-ketamine, one of the ketamine enantiomers, has a potent analgesic effect and weak side effects compared with R-ketamine. To date, analgesic potency of S-and R-ketamine was not been fully accounted for in the binding affinity to NMDA receptors. In the present review, we provide a novel analgesic mechanism of ketamine on chronic pain. Highlight: Spinal microglia after nerve injury activate Ca 2 þ -binding site of Ca 2 þ -activated K þ (BK) channels. S-ketamine significantly inhibited BK channel activation in spinal microglia. Intrathecal administration of BK channel activator mimics allodynia-like behavior, which was completely inhibited by S-ketamine. BK channel inhibitor alleviated neuropathic pain. BK channel inhibitor suppressed microglial activation in the spinal dorsal horn. Conclusion: These findings suggest that potent analgesic effects of S-ketamine arise from the inhibition of microglial BK channels, in addition to neuronal NMDA receptors. Thus, BK channels in microglia are a potential target for the treating of neuropathic pain.

Blockade of BK channels attenuates chronic visceral hypersensitivity in an IBS-like rat model

“…Activation of BK channels can reduce neuropathic pain and inflammatory pain 17,18 ; there are also studies showing that inhibition of BK channels can reduce neuropathic pain and morphine-induced hyperalgesia. 7,12 In this study, we found that BK channels contributed to the formation of IBS (Figure 2) and that blockade of the BK channels could inhibit visceral hyperalgesia induced by postnatal CRD (Figure 4).…”

“… 4 – 6 Studies have found that intrathecal injection of large-conductance calcium and voltage-dependent potassium ion channel (Big/Large-conductance Ca 2+ -activated K + channels, BK channels) blockers can relieve neuropathic pain. 7 The BK channel regulates membrane excitability and intracellular calcium ion signaling through selective connection of large BK α subunits and accessory β or γ subunits. 8 – 10 Recently, the full-length structure of the BK channel in the open state was analyzed by cryo-electron microscopy, which provides a more detailed structural basis for the study of the BK channel.…”

Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions

“…BK channels are also localized in the spinal cord [ 208 ] and cortical microglia [ 209 ]. In the spinal cord, BK can induce microglial hyperactivity related to neuropathic pain [ 210 ] and potentiate spinal synapses in lamina I spinal neurons [ 8 ].…”