Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing

Abstract

The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.

Slack K + channels attenuate NMDA‐induced excitotoxic brain damage and neuronal cell death

“…Hence, we showed in a previous study that global and sensory neuron‐specific Slack knockout mice (Slack KO) develop increased pain hypersensitivity in different models of neuropathic pain and, in addition, mice lacking Slack show altered nocifensive responses to stimulation of adenosine triphosphate (ATP)‐sensitive P 2 X 3 receptors. Inflammatory and acute nociceptive pain responses, however, were not affected by Slack deficiency 8,10,11,13,18,19 . We also demonstrated the importance of Slack for cognitive flexibility, locomotor activity, and the ability to properly adapt to unknown environments and experimental setups 6 .…”

“…Inflammatory and acute nociceptive pain responses, however, were not affected by Slack deficiency. 8,10,11,13,18,19 We also demonstrated the importance of Slack for cognitive flexibility, locomotor activity, and the ability to properly adapt to unknown environments and experimental setups. 6 Moreover, male Slack KO mice showed abnormal sociability in different social interaction tests.…”

Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch

“…At a holding potential of −70 mV, a series of 500 ms-long test pulses ranging from −120 to +120 mV in intervals of 20 mV were applied. [16] Our patch-clamp recordings revealed that the developed Slack activators (except compound 2) significantly increased the I K amplitude compared to the vehicle (Figure 1B and Figure S4, Supporting Information). At a voltage of +80 mV, the current densities of the compounds increased with a range between 2.0 to 14.8 fold compared to the baseline (Figure 1B).…”

The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice

“…However, the Randall-Selitto test was used to examine the mechanical pain by measuring tail withdrawal in the previous study, for which the equipment they used was not designed (Paw Pressure Randall Selitto Instrument, IITC Life Science) ( Lu et al, 2015 ). Also, another recent study from the same group used the von Frey test to measure mechanical pain sensitivity in the parsed nerve injury (SNI) model mice and naïve mice, which showed no different mechanical pain sensitivity in naive WT and Slack –/– mice without using the Randall Selitto test ( Lu et al, 2021 ). Thus, we believe in the soundness of the enhanced response to nociceptive mechanical stimuli in Slack –/– mice.…”

“…The Slack channel is richly expressed in the brain and dorsal root ganglia (DRG) ( Bhattacharjee et al, 2002 ; Tamsett et al, 2009 ; Lu et al, 2015 ) suggesting its involvement in pain sensing. The Slack channel is also reported expressed in IB4-positive central terminals in the spinal cord ( Lu et al, 2015 ; Lu et al, 2021 ).…”