A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

J Clin Invest. 2013 Sep;123(9):4050-62. doi: 10.1172/JCI70026. Epub 2013 Aug 27.


Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated Aβ-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory Aβ-fiber inputs onto PKCγ+ neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents Aβ input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by Aβ-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.

Publication types

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

MeSH terms

  • Animals
  • Feedback, Sensory*
  • Glycine Agents / pharmacology
  • Hyperalgesia / physiopathology*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Male
  • Nerve Net / physiopathology*
  • Neurons / enzymology
  • Nociception
  • Patch-Clamp Techniques
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / physiopathology*
  • Spinal Nerves / pathology
  • Spinal Nerves / physiopathology
  • Strychnine / pharmacology
  • Synaptic Transmission


  • Glycine Agents
  • protein kinase C gamma
  • Protein Kinase C
  • Strychnine