A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia
Yan Lu, … , Ru-Rong Ji, Lize Xiong
Yan Lu, … , Ru-Rong Ji, Lize Xiong
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):4050-4062. https://doi.org/10.1172/JCI70026.
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Research Article Neuroscience

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

Abstract

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.

Authors

Yan Lu, Hailong Dong, Yandong Gao, Yuanyuan Gong, Yingna Ren, Nan Gu, Shudi Zhou, Nan Xia, Yan-Yan Sun, Ru-Rong Ji, Lize Xiong

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Figure 3

Feed-forward excitatory connections from PKCγ+ neurons to nociceptive TC neurons are normally silent after Aβ-fiber stimulation.

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Feed-forward excitatory connections from PKCγ+ neurons to nociceptive TC...
(A) Unitary excitatory connection between PKCγ+ and TC neurons. post, postsynaptic; pre, presynaptic. (B) Confocal images show 30-μm-thick optical stacks of the recorded neuronal pair. Arrows indicate the PKCγ+ cell, and the arrowhead indicates putative axon. Insets indicate 1-μm-thick optical stacks of the PKCγ+ cell. Scale bar: 100 μm. (C) AP patterns of the recorded neurons. (D) Schematic diagram of the excitatory connection and the feed-forward inhibitory circuit. (E and F) DR stimulation at Aβ- or Aδ-fiber strength evokes a biphasic synaptic response in PKCγ+ neurons but fails to evoke a synaptic response in TC cell. (G) DR stimulation at C-fiber strength evokes monosynaptic C-fiber EPSPs in TC cell. The inset shows the consistent latency and lack of synaptic failure during 1-Hz trials. (H) Strychnine blocks the DR-evoked polysynaptic IPSPs and generates long-lasting EPSPs with APs in PKCγ+ neurons and recruits polysynaptic Aβ-fiber EPSPs in TC cells. The inset shows the variation of the latency and synaptic failure during 20-Hz trials. (I) Application of strychnine does not recruit additional C-fiber inputs, aside from the original C-fiber inputs in TC neurons. (J) Capsaicin evokes marked increases in mEPSC frequency in TC neurons but has no effect on PKCγ+ and Gly neurons.