xe-991--anthracenone and Bone-Neoplasms

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.

Topics: Acetylcholine; Animals; Anthracenes; Bone Neoplasms; Carbamates; Disease Models, Animal; Female; Hyperalgesia; KCNQ Potassium Channels; Membrane Transport Modulators; Neoplasm Transplantation; Pain; Phenylenediamines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Spinal Cord

Bone cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying bone cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of bone cancer pain. By using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in bone cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in bone cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes bone cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of bone cancer pain.

Topics: Animals; Anthracenes; Bone Neoplasms; Carbamates; Carcinoma; Down-Regulation; Female; Ganglia, Spinal; Hot Temperature; Hyperalgesia; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Mammary Neoplasms, Experimental; Neoplasm Transplantation; Nociception; Pain; Patch-Clamp Techniques; Phenylenediamines; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Stress, Mechanical; Synaptic Transmission; Tibia