Background & Aims

Chronic pain is a significant challenge, with limited effective treatment options. Despite recent progress in understanding the biology of pain, current medications often have unwanted side effects on the central nervous system. Consequently, there is increasing interest in studying mechanisms and therapeutic targets for pain in the peripheral nervous system as a promising approach to develop new, more effective, and safer treatments. Within the peripheral nervous system, satellite glial cells (SGCs) are abundant cells in the peripheral dorsal root ganglia (DRG) that surround the cell bodies of sensory neurons responsible for detecting sensations like touch, heat, and pain. SGCs play important roles in maintaining the homeostasis of these neurons and have been implicated in the development of chronic pain. However, despite their significance, our understanding of SGC biology and their therapeutic potential remains limited.

Methods

Single-cell RNA sequencing has revealed new traits of SGCs in DRG tissues, including high expression of diazepam binding inhibitor (DBI), which may enhance communication between satellite glia and sensory neurons (Tonello et al. 2023). DBI can modulate ?-aminobutyric acid type-A (GABA) receptors, strengthening inhibitory synapses in the brain. Local GABAergic signaling in DRG is now viewed as a potential target for chronic pain relief (Du et al. 2017). In this study, we utilized mice, rats, and human DRG tissues to examine the expression of DBI and its signaling. Our methods included immunofluorescence, fluorescence in situ hybridization, cell cultures, and patch clamp recording. We also established experimental models of inflammatory and neuropathic pain. Behavioral tests were conducted to evaluate pain responses and the therapeutic value of DBI.

Results

we report that the diazepam binding inhibitor (DBI) is specifically expressed in SGCs of mice, rats, and humans, but not in sensory neurons or other DRG cells. Knockdown of DBI leads to hypersensitivity to touch without affecting other sensory modalities. In animal models of inflammatory and neuropathic pain, overexpression of DBI in DRG significantly alleviates hypersensitivity to touch (i.e. mechanical allodynia). DBI acts as a partial agonist and positive allosteric modulator at neuronal GABA A receptors, particularly those with a high-affinity benzodiazepine binding site. These receptors are selectively expressed by a subpopulation of sensory neurons that detect touch stimuli, suggesting a mechanism for the specific effect of DBI on this modality.

Conclusions

Overall, this study reveals the role of DBI in SGC-sensory neuron crosstalk in DRG and its role in modulating touch and pain. These findings may offer a therapeutic target for safer and more effective treatment of chronic pain.

References

-Tonello et al. Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain. Brain Behav. Immun. 2023. PMCID: PMC10530626
-Du et al. Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J Clin Invest. 2017. PMCID: PMC5409786.

Presenting Author

Arthur Prudente

Poster Authors

Arthur Prudente

PhD

University of Cincinnati

Lead Author

Xinmeng Li

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

Lead Author

Vincenzo Prato

PhD

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Xianchuan Guo

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

Lead Author

Han Hao

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

Lead Author

Frederick Jones

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Sofia Figoli

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Pierce Mullen

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Yujin Wang

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

Lead Author

Raquel Tonello

New York University

Lead Author

Sanghoon Lee

Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, USA

Lead Author

Shihab Shah

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Benito Maffei

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Xiaona Du

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

Lead Author

Nikita Gamper

Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK

Lead Author

Temugin Berta

Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, USA

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology