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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

Sdrulla, Andrei D.a; Xu, Qianb,c; He, Shao-Qiua; Tiwari, Vinoda; Yang, Feia; Zhang, Chena,d; Shu, Bina; Shechter, Ronena; Raja, Srinivasa N.a; Wang, Yund; Dong, Xinzhongb,c; Guan, Yuna,*

doi: 10.1097/01.j.pain.0000460353.15460.a3
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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.

This study suggests that electrical stimulation of low-threshold Aβ-fibers induces prolonged inhibition of excitatory postsynaptic current evoked by high-threshold afferent inputs in lamina II neurons.

aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

bThe Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

cHoward Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

dDepartment of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

Corresponding author. Address: Division of Pain Medicine, Department of Anesthesiology/CCM, the Johns Hopkins University, 720 Rutland Ave, Ross 350, Baltimore, MD 21205, USA. Tel.: 410-502-5510; fax: 410-614-2109. E-mail address: yguan1@jhmi.edu (Y. Guan).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received October 21, 2014

Received in revised form December 03, 2014

Accepted December 19, 2014

© 2015 International Association for the Study of Pain
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