Suppression of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the sensitization of dorsal horn WDR neurons and pain hypersensitivity in a rat model of bone cancer pain

Abstract

Primary and metastatic cancers that affect bones are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. In the present study, we investigated whether inhibition of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the development of bone cancer pain via sensitization of dorsal horn wide dynamic range (WDR) neurons. Using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumor cells, we observed a significant increase in C-fiber responses of dorsal horn WDR neurons in the MRMT-1 injected rats, indicating sensitization of spinal WDR neurons in bone cancer rats. Furthermore, we discovered that blockade of KCNQ/M channels in the spinal cord by local administration of XE-991, a specific KCNQ/M channel blocker, caused a robust increase in excitability of dorsal horn WDR neurons, while, producing obvious pain hypersensitivity in normal rats. On the contrary, activation of spinal KCNQ/M channels by retigabine, a selective KCNQ/M channel opener, not only inhibited the bone cancer‑induced hyperexcitability of dorsal horn WDR neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in the bone cancer rats, while all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. All things considered, these results suggest that suppression of KCNQ/M channels in the spinal cord likely contributes to the development of bone cancer pain via sensitization of dorsal horn WDR neurons in rats following tumor cell inoculation.

Suppression of KCNQ/M Potassium Channel in Dorsal Root Ganglia Neurons Contributes to the Development of Osteoarthritic Pain

“…Consistent with a previous report showing that expression of KCNQ2 and KCNQ3 channels is markedly suppressed in DRG neurons of bone cancer model rats [6,21], our data show a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNA in osteoarthritic rat DRG neurons. Clinical and experimental observations implicate the increased excitability of DRG neurons as a probable substrate of persistent neuropathic pain [22].…”

M‐type K+ channels in peripheral nociceptive pathways

“…As in the case of neuropathic pain, a marked down‐regulation of K v 7.2 and K v 7.3 channel abundance and a reduction of M current amplitudes were reported in DRG neurons in a rat model of bone cancer pain (Zheng et al, ); these effects were also accompanied by a hyperexcitable state of the DRG neurons. In a follow‐up study, the same group also showed that the excitability of the C‐fibre‐synapsed WDR neurons in the dorsal horn is also enhanced in the rats developing bone cancer and this effect was also attributed, at least in part, to the M channel suppression (although in the latter study, it was not clear, whether the M current was down‐regulated in the C‐fibre terminals or in the WDR neurons themselves, or at both locations) (Cai et al, ). Systemic (Zheng et al, ) or intrathecal (Cai et al, ) retigabine alleviated mechanical allodynia and thermal hyperalgesia induced by bone cancer and also reduced hyperexcitability of both DRG and WDR DH neurons.…”

Current Status of the New Antiepileptic Drugs in Chronic Pain

“…Opening of these channels by RTG leads to hyperpolarization of the cell membrane, and a resultant decrease in cell excitability. A number of recent studies have reported that RTG can relieve pain-like behaviors such as hyperalgesia and allodynia in animal models of neuropathic pain (Takeda et al, 2011; Abd-Elsayed et al, 2015; Cai et al, 2015). Although several different types of neuropathic pain animal models have been developed and extensively studied, but still we fails to identify the common therapeutic molecular target among the voltage gated K + channels (Kv7) in the neurons located in the nociceptive pathway.…”