Peripheral gating of mechanosensation by glial diazepam binding inhibitor
Xinmeng Li, … , Xiaona Du, Nikita Gamper
Xinmeng Li, … , Xiaona Du, Nikita Gamper
Published June 18, 2024
Citation Information: J Clin Invest. 2024;134(16):e176227. https://doi.org/10.1172/JCI176227.
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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 2

Knockdown of Dbi induces mechanical hypersensitivity in mice.

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Knockdown of Dbi induces mechanical hypersensitivity in mice. (A–E) siRN...
(A–E) siRNA against Dbi (or a non-targeting control siRNA) was intrathecally injected (2 mg/site), and 48 hours later the following tests were performed: mechanical sensitivity (von Frey) test (A), cold allodynia (dry ice) test (B), Hargreaves test (C), adhesive removal test (tape assay) (D), and alligator clip test (E). Bars are mean ± SEM. *P < 0.05; **P < 0.01, significant difference for groups indicated by the connector line (unpaired t test). (F) Recovery of mechanical hypersensitivity (von Frey test) induced by intrathecal siRNA knockdown of DBI with intrathecal injection of recombinant DBI (10 ng/site). ###P < 0.001, significant difference from baseline; **P < 0.01, ***P < 0.001, significant difference from time-matched saline group (2-way repeated-measures ANOVA with Šidák’s post hoc test). (G) Schematic timeline for the viral DRG gene delivery and osmotic minipump experiment. Inset depicts DRG 8 weeks after injection with AAV9-U6-shDBI-CAG-EGFP virions; this image is included in the extended data set in Supplemental Figure 4A. Scale bars: 50 μm. (H) Mechanical sensitivity was monitored with the von Frey test during 42 days after the DRG injection of AAV9-U6-shDBI-CAG-EGFP virions or GFP control virions (1.1 × 1012 to 1.2 × 1012 viral genomes/mL; 2 μL). ***P < 0.001, significant difference from time-matched control group (2-way repeated-measures ANOVA with Tukey’s post hoc test). (I) Similar to H, but heat sensitivity was tested with the Hargreaves test. (J and K) Mechanical (J) and heat (K) sensitivity was monitored after the implantation of osmotic minipumps delivering recombinant DBI to the DRG (200 μM, 0.5 μL/h; see Methods) to the mice preinjected with the AAV9-U6-shDBI-CAG-EGFP virions. *P < 0.05; **P < 0.01, significant difference from time-matched control group (2-way repeated-measures ANOVA with Tukey’s post hoc test).