Epigenetic restoration of voltage‐gated potassium channel Kv1.2 alleviates nerve injury‐induced neuropathic pain

Abstract

Voltage‐gated potassium channels (Kv) are important regulators of neuronal excitability for its role of regulating resting membrane potential and repolarization. Recent studies show that Kv channels participate in neuropathic pain, but the detailed underlying mechanisms are far from being clear. In this study, we used siRNA, miR‐137 agomir, and antagomir to regulate the expression of Kv1.2 in spinal cord and dorsal root ganglia (DRG) of naïve and chronic constriction injury (CCI) rats. Kv currents and neuron excitability in DRG neurons were examined by patch‐clamp whole‐cell recording to verify the change in Kv1.2 function. The results showed that Kv1.2 was down‐regulated in DRG and spinal dorsal horn (SDH) by CCI. Knockdown of Kv1.2 by intrathecally injecting Kcna2 siRNA induced significant mechanical and thermal hypersensitivity in naïve rats. Concomitant with the down‐regulation of Kv1.2 was an increase in the expression of the miR‐137. The targeting and regulating of miR‐137 on Kcna2 was verified by dual‐luciferase reporter system and intrathecal injecting miR‐137 agomir. Furthermore, rescuing the expression of Kv1.2 in CCI rats, achieved through inhibiting miR‐137, restored the abnormal Kv currents and excitability in DRG neurons, and alleviated mechanical allodynia and thermal hyperalgesia. These results indicate that the miR‐137‐mediated Kv1.2 impairment is a crucial etiopathogenesis for the nerve injury‐induced neuropathic pain and can be a novel potential therapeutic target for neuropathic pain management.

The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids

“…112,113 In the same way, the activation of voltage-gated potassium (Kv) channels is another strategy to alleviate chronic pain. [114][115][116] The participation of ATP-sensitive K+ channels in HO-carbon monoxide pathway-induced antinociception has been demonstrated by the reversion of the antinociceptive activity of hemin with the local injection of the ATP-sensitive K+ channel antagonist glibenclamide. 117 Accordingly, and considering that CORM-3 is capable of inhibiting NaV channels in alveolar epithelial cells 118 and activating Kv channels in the endothelium of cirrhotic animals, 119 the participation of NaV and/or Kv channels in the mitigation of chronic pain induced by CO-RMs might be another possible mechanism of action for further investigation.…”

“…The participation of some voltage‐gated sodium channel (NaV) channel subtypes in chronic pain disorders and the NaV modulators as new drugs for the treatment of chronic pain is well documented 112,113 . In the same way, the activation of voltage‐gated potassium (Kv) channels is another strategy to alleviate chronic pain 114–116 . The participation of ATP‐sensitive K+ channels in HO‐carbon monoxide pathway‐induced antinociception has been demonstrated by the reversion of the antinociceptive activity of hemin with the local injection of the ATP‐sensitive K+ channel antagonist glibenclamide 117 .…”

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

“…(v) K v 1.2 function may be controlled by the non-coding miniature RNA miR-137. Because it impairs K v 1.2 function, experimental impairment of miR-137 function, rescues channel expression and function and attenuates allodynia in rats subject to CCI (258). (vi) A long non-coding RNA (Kcna2 antisense RNA) contributes to neuropathic pain by silencing the KCNA2 gene and thereby reducing expression of K v 1.2 in primary afferents (259).…”

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

“…Knockdown of K v 1.2 by siRNA induces significant mechanical and thermal hypersensitivity in naive rats (Zhang et al, 2020) and considerable progress has been made in understanding the underlying epigenetic mechanisms. Three of these involve alterations in DNA methylation.…”

“…There is also evidence that K v 1.2 function is controlled by the non-coding miniature RNA miR-137. Because it impairs K v 1.2 function, experimental impairment of miR-137 function, rescues channel expression and function attenuates allodynia in rats subject to CCI (Zhang et al, 2020).…”