Increased c-fos immunoreactivity in the spinal cord and brain following spinal cord stimulation is frequency-dependent.

Spinal cord stimulation (SCS) is an alternative approach for treatment of neuropathic pain when conservative management is ineffective. Previously we showed both 4 Hz and 60 Hz SCS reduces hyperalgesia in an animal model of neuropathic pain. However, the mechanisms underlying the pain reduction by SCS and how different frequencies of SCS produce the analgesic effect are unclear. To elucidate potential sites modulated by SCS we examined distribution of c-fos in Sprague-Dawley rats with spared nerve injury (SNI) and those without injury in response to SCS. SCS was delivered at one of 3 different frequencies (4 Hz, 60 Hz, and 100 Hz) for 30 min 2 weeks after SNI or in animals without SNI. Animals were perfused either 5 min or 2 h after SCS and c-fos protein examined immunohistochemically. The number of c-fos positive cells significantly increased 5 min (35 min after SCS began) after 4 Hz SCS in the NRM, but not PAG in animals with nerve injury. The number of c-fos positive cells was significantly increased bilaterally 2 h after either 4 Hz or 60 Hz SCS in the spinal cord dorsal horn in the cervical enlargement and under the electrode, but not in the lumbar enlargement in animals with nerve injury. In uninjured animals 4 Hz SCS increased c-fos expression at the electrode site and lumbar enlargement when compared to animals implanted with the electrode who did not receive SCS. 100 Hz SCS had no effect on c-fos expression. Thus, at the time points examined in this model, low frequency SCS likely activates supraspinal and spinal mechanisms to produce analgesia, while higher frequencies activate spinal mechanisms.