title: Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high-threshold afferent inputs in mice.
abstract: Electrical stimulation of low-threshold Aβ-fibers (Aβ-ES) is used clinically to treat neuropathic pain conditions that are refractory to pharmacotherapy. However, it is unclear how Aβ-ES modulates synaptic responses to high-threshold afferent inputs (C-, Aδ-fibers) in superficial dorsal horn. Substantia gelatinosa (SG) (lamina II) neurons are important for relaying and modulating converging spinal nociceptive inputs. We recorded C-fiber-evoked excitatory postsynaptic currents (eEPSCs) in spinal cord slices in response to paired-pulse test stimulation (500 μA, 0.1 millisecond, 400 milliseconds apart). We showed that 50-Hz and 1000-Hz, but not 4-Hz, Aβ-ES (10 μA, 0.1 millisecond, 5 minutes) induced prolonged inhibition of C-fiber eEPSCs in SG neurons in naive mice. Furthermore, 50-Hz Aβ-ES inhibited both monosynaptic and polysynaptic forms of C-fiber eEPSC in naive mice and mice that had undergone spinal nerve ligation (SNL). The paired-pulse ratio (amplitude second eEPSC/first eEPSC) increased only in naive mice after 50-Hz Aβ-ES, suggesting that Aβ-ES may inhibit SG neurons by different mechanisms under naive and nerve-injured conditions. Finally, 50-Hz Aβ-ES inhibited both glutamatergic excitatory and GABAergic inhibitory interneurons, which were identified by fluorescence in vGlut2-Td and glutamic acid decarboxylase-green fluorescent protein transgenic mice after SNL. These findings show that activities in Aβ-fibers lead to frequency-dependent depression of synaptic transmission in SG neurons in response to peripheral noxious inputs. However, 50-Hz Aβ-ES failed to induce cell-type-selective inhibition in SG neurons. The physiologic implication of this novel form of synaptic depression for pain modulation by Aβ-ES warrants further investigation.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, USA Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Andrei D
authors.initials: AD
authors.lastname: Sdrulla
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Shao-Qiu
authors.initials: SQ
authors.lastname: He
authors.forename: Vinod
authors.initials: V
authors.lastname: Tiwari
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Shu
authors.forename: Ronen
authors.initials: R
authors.lastname: Shechter
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000502:physiology*; D009437:Neuralgia / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology; D013127:Spinal Nerves / Q000503:physiopathology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D001640:Bicuculline; D018683:Excitatory Amino Acid Agents; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase; D018684:Glycine Agents; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D050599:Vesicular Glutamate Transport Protein 2; D000097573:Red Fluorescent Protein; C493477:Slc17a6 protein, mouse