title: Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.
abstract: Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina;
authors.forename: Tianhe C
authors.initials: TC
authors.lastname: Zhang
authors.affiliation: Stryker Corporation, Kalamazoo, Michigan.
authors.forename: John J
authors.initials: JJ
authors.lastname: Janik
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina;
authors.forename: Ryan V
authors.initials: RV
authors.lastname: Peters
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina; Department of Anesthesiology, Duke University, Durham, North Carolina; and.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina; Department of Anesthesiology, Duke University, Durham, North Carolina; and.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina; Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina; Department of Neurobiology, Duke University, Durham, North Carolina; Department of Surgery, Duke University, Durham, North Carolina; warren.grill@duke.edu.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Grill
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003198:Computer Simulation; D004195:Disease Models, Animal; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008159:Lumbar Vertebrae; D008297:Male; D008839:Microelectrodes; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology* / Q000628:therapy; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology*; D062187:Spinal Cord Stimulation / Q000379:methods
chemical_list: D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001640:Bicuculline
keywords: Gate Control Theory; chronic pain; computational modeling; spinal cord stimulation; spinal microcircuits