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

Pain. 2015 Jun;156(6):1008-1017. doi: 10.1097/01.j.pain.0000460353.15460.a3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Bicuculline / pharmacology
  • Disease Models, Animal
  • Electric Stimulation / methods*
  • Excitatory Amino Acid Agents / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Glycine Agents / pharmacology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Fibers / physiology*
  • Neuralgia / pathology
  • Neuralgia / physiopathology*
  • Neuralgia / therapy
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / physiology*
  • Sensory Thresholds / drug effects
  • Sensory Thresholds / physiology
  • Spinal Cord / pathology
  • Spinal Nerves / physiopathology
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism


  • Excitatory Amino Acid Agents
  • GABA-A Receptor Antagonists
  • Glycine Agents
  • Luminescent Proteins
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • red fluorescent protein
  • Green Fluorescent Proteins
  • Glutamate Decarboxylase
  • Bicuculline