Dorsal root ganglion neuromodulation restores accumbal gate to inhibit mechanical allodynia

Mechanical allodynia refers to a hypersensitive status in response to innoxious stimuli caused by neuropathic pain. A therapeutic strategy to reverse the sensory impairment is neuromodulation treatment selectively targeting the dorsal root ganglion. However, the supra-spinal mechanism of neuromodulation therapy remains elusive. By combination of the multiple-channel neurophysiology recording and cellular manipulation in freely moving rats, we investigated the gate function of nucleus accumbens in control of nociceptive inputs, and its role in pulsed-radiofrequency neuromodulation therapy for neuropathic pain, using a clinically relevant neuromodulation parameter. We initially identified a gaining representation of the nucleus accumbens in response to nociceptive (pinprick), but not innoxious inputs (4 g Von Frey filament) in naïve rats. In neuropathic pain condition, the gate function was disrupted to drive an enhancement of accumbal activity during mechanical allodynia behavior. Pulsed radiofrequency neuromodulation of dorsal root ganglion was utilized to reverse pain hypersensitivity and accumbal homeostasis. Furthermore, we found that the accumbal gaining was not only a dynamic integration of painful signals, but also to serve as a gate of nociceptive perception required for neuromodulation therapy. In addition, the supra-spinal modulation effect on allodynic phenotype was imitated through optogenetic activation of the accumbal terminals of the spinal cord projections. Our data indicates that the accumbal gate is essential for integration and control of sensory inputs, potentially acting as one neuromodulatory target to reverse pain sensitization.