Peripheral gating of mechanosensation by glial diazepam binding inhibitor
Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper
Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper
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Research Article Neuroscience

Peripheral gating of mechanosensation by glial diazepam binding inhibitor

Abstract

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.

Authors

Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper

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Figure 7

DBI-induced filtering of peripheral nerve activity at the DRG.

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DBI-induced filtering of peripheral nerve activity at the DRG. (A) Schem...
(A) Schematic of the recording method. Experiments were performed in mice. Spinal nerve and dorsal root were surgically exposed and then individually suspended on fine hook electrodes; DRG was exposed to direct drug application. (B) Subthreshold mechanical stimulus (von Frey filament, 0.6 g) increased firing frequency in both spinal nerve and dorsal root branches of the nerve (middle traces, as compared with basal activity shown in the top traces). Application of DBI (200 μM, 2 μL) to the DRG reduced mechanical stimulus–induced firing frequency in the dorsal root but not in the spinal nerve (bottom traces). (C) Histogram of firing frequencies of spinal nerve and dorsal root branches of the nerve from experiment exemplified in B. (D) Summary of experiments exemplified in B. (E–G) Experiment similar to that shown in B–D, but a noxious mechanical stimulus (needle prick) was used. (H–J) Experiment similar to those shown above, but a noxious thermal stimulus (hot water, 60°C) was used instead of mechanical stimuli. One-way repeated-measures ANOVA with Tukey’s post hoc test. (D, G, and J) *P < 0.05, **P < 0.01, significant difference from previous group.