Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

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 2ϩ -activated K ϩ (K Ca ) currents in microglia, which are known to 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.

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

“…Expression of DREADDs before neuropathic pain induction prevented injury-induced recruitment of monocyte-derived cells from contributing to the observed effects. Although we predict that G i -linked signaling inhibits Ca 2+ influx in microglia to attenuate proinflammatory cytokine production (43,44), the precise mechanisms are the subject of ongoing investigation. Because microglial activity has not been selectively manipulated in any prior study, these data, to our knowledge, are the first to unequivocally implicate microglia in a pathological pain state.…”

“…Transfection of the G i or control constructs occurred before experimental manipulation, to ensure that microglia would form the majority of CD68 + cells in the spinal cord (40,41). G i -linked signaling was predicted to attenuate microglial reactivity because activation of the M4 muscarinic receptor [the G i DREADD progenitor (39)] inhibits Ca 2+ influx in parasympathetic neurons (42), a process associated with decreased proinflammatory cytokine production in microglia (43,44). DREADD expression was restricted to Iba1 + cells in the lumbar dorsal spinal cord (Fig.…”

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

“…The incision was washed with saline and closed. Intrathecal administration was performed using a 25 l Hamilton syringe with a 30 gauge needle according to the methods described previously (Hayashi et al, 2011).…”

“…The 50% PWT values were calculated using the up-down method. The PWT was measured on both the right and the left paw for the intrathecal administration of CGA (10 nM, 5 l), ATP (100 nM, 10 l), or LPA (200 M, 5 l) with the wild-type and CatBϪ/Ϫ mice, and the mean was calculated (Chaplan et al, 1994, Hayashi et al, 2011.…”

The Use of Ketamine in Neuropathic Pain

“…channels [34], and dopamine receptors, as well as other cholinergic, purinergic and adenosine receptor systems [25,35]. The ability of ketamine to block conductance of specific ion channels may be the reason it has local anesthetic properties after topical administration [36].…”