Background: Neuromodulation therapies offer a treatment option that has minimal side effects and is relatively safe and potentially reversible. Spinal cord stimulation (SCS) has been used to treat various pain conditions for many decades. High-frequency SCS (HFSCS) involves the application of a single waveform at 10,000 Hz at a subthreshold level, therefore providing pain relief without any paresthesia. Methods: We tested whether early HFSCS treatment attenuated spared nerve injury (SNI)-induced neuropathic pain. The phosphorylation profile of mitogen-activated protein kinases (MAPKs), i.e., extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38, was evaluated to elucidate the potential underlying mechanism. Results: SNI of rat unilateral sciatic nerves induced mechanical hyperalgesia in the ipsilateral hind paws. Rats were assigned to SCS sessions with HFSCS (frequency 10 kHz; pulse width 30 μs; pulse shape of charge-balanced, current controlled; delivered continuously for 72 h), or sham stimulation immediately after SNI. Tissue samples were examined at 1, 3, 7, and 14 days after SNI. Behavioral studies showed that HFSCS applied to the T10/T11 spinal cord significantly attenuated SNI-induced mechanical hyperalgesia compared with the sham stimulation group. Moreover, western blotting revealed a significant attenuation of the activation of ERK1, ERK2, JNK1, and p38 in the dorsal root ganglia and the spinal dorsal horn. Conclusion: Application of HFSCS provides an effective treatment for SNI-induced persistent mechanical hyperalgesia by attenuating ERK, JNK, and p38 activation in the dorsal root ganglia and the spinal dorsal horn.
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