Surround Inhibition Mediates Pain Relief by Low Amplitude Spinal Cord Stimulation: Modeling and Measurement

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating ther-apeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds–minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthe-tized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influ-enced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at;80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the com-plement of DC axons activated, and on stimulation parameters. Intrathecal administration of bicuculline shifted neural responses to low-amplitude stimulation in both the model and experiment, suggesting that analgesia is dependent on segmental GABAergic mechanisms. Our results support the hypothesis that low-frequency subperception SCS generates rapid analgesia by activating a small number of DC axons which inhibit DH neuron activity via surround inhibition.