Slack Channels Expressed in Sensory Neurons Control Neuropathic Pain in Mice

Abstract

Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that modulating its activity might represent a novel strategy for management of neuropathic pain.

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice

“…The absence of any motor coordination deficits is in line with our previous study showing that lack of Slack does not affect the performance on an accelerating rotarod (Lu et al 2015).…”

“…Since most of the tests studying unconditioned anxiety largely depend on normal explorative behavior and locomotion, it is presently difficult for us to estimate the impact of endogenous Slack channels in regulating anxiety by studying our global Slack mutant mouse model. Future studies on tissue-specific Slack KOs that show a normal explorative behavior but selectively lack Slack channels in brain regions involved in anxiety-related neuronal circuits (e.g., the amygdala or the prefrontal cortex) will be required to adequately address this issue (Lu et al 2015).…”

“…Slack-deficient mice were generated by a targeted ablation of Kcnt1 in murine embryonic stem cells in combination with a common Cre/loxP-system as described previously (Lu et al 2015). Experimental mice were back crossed for at least six generations to a C57BL/6N background before they were used for expression analysis or behavioral experiments.…”

“…To test whether expression of Slack channels is required for spatial memory or motor performance, we have now studied recently generated Kcnt1 null mice (Slack KOs) (Lu et al 2015), and compared their behavior with that of age-matched wild-type (WT) mice. Our data suggest that complex learning processes, including reversal learning in the Morris water maze (MWM) task, locomotor activity, and coping with unfamiliar environments and situations require endogenous Slack channels.…”

International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels

“…The channel is also expressed at high levels in nociceptive neurons within the dorsal root ganglion, and suppression of current using several approaches, including deletion of the gene for K Na 1.1, enhances neuronal excitability and produces hypersensitivity of animals to several pain-inducing stimuli (Gao et al, 2008;Tamsett et al, 2009;Nuwer et al, 2010;Huang et al, 2013;Lu et al, 2015;Martinez-Espinosa et al, 2015). Deletion of the gene in mice also has a variety of more wide-ranging effects on behavior, including an inability to reverse a previously learned behavior (Bausch et al, 2015).…”