Biology subjects

Demeter, J. B.

Publications and source records attributed to Demeter, J. B..

3 recordsLinked to original sources

bioRxiv2025

The circular RNA landscape of human dorsal root ganglia and its association with opioid exposure

Opioids are among the most widely prescribed treatments for pain; however, prolonged use leads to adverse effects, including reduced analgesic efficacy (tolerance) and paradoxically heightened pain sensitivity (opioid-induced hyperalgesia, OIH). Neurons that detect noxious stimuli within the dorsal root ganglion (DRG), referred to as nociceptors, mediate both the beneficial and maladaptive effects of opioids. Although post-transcriptional regulation is critical for DRG function, the role of circular RNAs (circRNAs)--an evolutionarily conserved and highly stable class of RNA--in nociceptive processes remains largely unexplored in humans. Further, how opioids might alter the circRNA landscape of human DRG (hDRG) is unknown. To address this gap, we performed high-coverage RNA sequencing on hDRG tissue obtained from opioid-positive organ donors and compared these profiles with those from age- and sex-matched opioid-negative controls. The circRNA expression profiles were analyzed using the CIRI2/CIRIquant pipeline, and parallel measurements were made for the linear transcriptome (e.g. mRNA). Our data revealed a significant overall decrease in circRNA abundance in the opioid-exposed group. Among the top differentially expressed circRNAs (FDR [≤] 0.05) were circSH3D19, circSMARCA5, circHLA-A, and circAMY2B, with an additional 39 circRNAs (p [≤] 0.005) altered in opioid-exposed tissue. To explore potential interactions with the linear transcriptome, we constructed a competing endogenous RNA (ceRNA) network using established pipelines and databases (circAtlas, miRanda, TargetScan, PITA, and miRDB). Gene Ontology enrichment analysis of predicted mRNA targets of these circRNAs identified overrepresented pathways related to neuronal development, synaptic signaling, inflammatory processes, and pain perception. These findings suggest that circRNAs may play a key regulatory role in the DRGs response to opioid exposure and modulation of pain. Future studies will investigate the spatial and temporal dynamics and functional and behavioral effects of these circRNA.

molecular biology↗

bioRxiv2024

Neuroimmune mechanisms of a mouse model of chronic back pain

Chronic back pain (CBP) is the leading cause of disability affecting 1 in 10 people worldwide. Symptoms are marked by persistent lower back pain, reduced mobility, and heightened cold sensitivity. Here, we utilize a mouse model of CBP induced by injecting urokinase-type plasminogen activator (uPA), a proinflammatory agent in the fibrinolytic pathway, between the L2/L3 lumbar vertebrae. We identified neuroimmune interactions contributing to uPA-induced CBP (henceforth, uPA-CBP) in mouse dorsal root ganglia (DRG), where nociceptive neurons reside. Flow cytometric data reveal that uPA-CBP increases CD45+CD11b+ cells in the DRG, a population characteristically implicated in other chronic pain models1. Blocking colony stimulating factor 1 receptor (CSF1R) signaling using PLX5622 partially reduced pain, suggesting CD45+CD11b+ macrophage involvement. Whole-cell patch-clamp electrophysiology data indicated DRG neuron hyperexcitability in CBP mice compared to controls. RNA sequencing revealed upregulation of pain- and inflammation-related genes involved in leukocyte migration. Together, these findings underscore the importance of the DRG neuroimmune axis in mediating chronic back pain. HighlightsO_LIuPA-CBP induces gait changes, mechanical and thermal sensitivity compared to shams C_LIO_LIuPA-CBP mice show increased CD45+CD11b+ cells in DRG compared to shams C_LIO_LIuPA-CBP mice show neuronal excitability in DRG neurons compared to shams C_LIO_LIPain behaviors are alleviated by pharmacologically blocking CSF1R signaling C_LIO_LIDysregulation of inflammation- and ion channel-related genes in uPA-CBP DRG C_LI

neuroscience↗

bioRxiv2024

Gabapentin's Effect on Human Dorsal Root Ganglia: Donor-Specific Electrophysiological and Transcriptomic Profiles

Neuropathic pain affects approximately 10% of the adult population and is commonly treated with gabapentin (GBP), a repurposed anticonvulsant drug. Despite its widespread clinical use, GBPs efficacy varies significantly among patients, highlighting the need to better understand its functional and molecular impacts on human pain-sensing neurons. In this study, we characterized the electrophysiological and transcriptomic effects of GBP on primary sensory neurons derived from the dorsal root ganglia (DRG) of ethically consented human donors. Using patch-clamp electrophysiology, we demonstrated that GBP treatment reduced neuronal excitability, with more pronounced effects in multi-firing vs. single-firing neuronal subtypes. Notably, significant donor-specific variability was observed in electrophysiological responsiveness to GBP treatment in vitro. RNA sequencing of DRG tissue from the GBP-responsive donor revealed differences in the transcriptome-wide expression of genes associated with ion transport, synaptic transmission, inflammation, and immune response relative to non-responsive donors. Cross-transcriptomic analyses further showed that GBP treatment counteracted these altered processes, rescuing aberrant gene expression at the pathway level and for several key genes. This study provides a comprehensive electrophysiological and transcriptomic profile of the effects of GBP on human DRG neurons. These findings enhance our understanding of GBPs mechanistic actions on peripheral sensory neurons and could help optimize its clinical use for neuropathic pain management.

neuroscience↗