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