Targeting A-type K+ channels in primary sensory neurons for bone cancer pain in a rat model

Abstract

Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K(+) channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K(+) channels in DRG neurons during bone cancer pain. The A-type K(+) currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K(+) channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K(+) currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K(+) channel blocker 4-AP or pandinotoxin-Kα, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K(+) channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K(+) channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain.

Kv3.4 channel function and dysfunction in nociceptors

“…10,11,[22][23][24][25] However, in contrast to Kv3.4 currents, these currents are low voltage-activated and are generally eliminated in our recordings by a conditioning pulse to ¡30 mV. 5,22 Evidence of their presence is apparent in the steady-state inactivation curve, which typically exhibits 2 Table 1.…”

“…5 Others also found Kv3.4 immunoreactivity and mRNA expression in these neurons. [9][10][11]21 We isolated the rat A-type Kv3.4 current and determined its molecular identity.…”

“…[1][2][3][4][5][6] In dorsal root ganglion (DRG) nociceptors, we showed that Kv3.4 currents can be easily isolated and that Kv3.4 channels are dysregulated following spinal cord injury (SCI). 7,8 Previous to this work, Kv3.4 was detected in DRG neurons via immunohistochemistry, western blot and RT-PCR, [9][10][11] but there was no compelling isolation of the corresponding K C current. In the whole-cell configuration, a subtraction protocol revealed a Kv3.4-like current in small-diameter nociceptors.…”

“…8,10,11 In the light of the physiological roles discussed above, the loss of Kv3.4 channels in nociceptors could contribute to enhanced firing rates and broadening of the AP, which would promote pain sensitization. Essentially, the loss of homeostatic analgesia that depends on the Kv3.4 channel and its modulation by PKC is conducive to the development of persistent peripheral hyperexcitability and persistent pain (Fig.…”

“…7 Implicating the Kv3.4 channel in pain pathology, several studies have found reduced expression of this K C channel in various models of persistent neuropathic Keywords: action potential, Kv3.4, pain, potassium channel, spinal cord injury pain. 8,10,11 Chien et al supported this link further by demonstrating that intrathecal injection of anti-sense Kv3.4 oligonucleotides induces mechanical hypersensitivity in rats. 11 Following SCI, we showed that Kv3.4 currents in DRG nociceptors are downregulated and additionally exhibit phenotype switching from fast inactivating A-type to delayed rectifier-type.…”