Targeting Histamine H3 Receptors to Suppress NGF-Driven Hyperexcitability in Neuropathic Pain

Kumar, A.; Kumar, R.; Kumari, P.; Bagade, A.; Yadav, A.; Kumar, B. A.; Dogra, S.; Umrao, D.; Copits, B. A.; Zorumski, C. F.; Mennerick, S.; Yadav, P. N.

doi:10.64898/2026.08.28.746833

bioRxiv · 10.64898/2026.08.28.746833

Targeting Histamine H3 Receptors to Suppress NGF-Driven Hyperexcitability in Neuropathic Pain

Kumar, A.·Kumar, R.·Kumari, P.·Bagade, A.·Yadav, A.·Kumar, B. A.·Dogra, S.·Umrao, D.·Copits, B. A.·Zorumski, C. F.·Mennerick, S.·Yadav, P. N.

View original source ↗Export metadata ↓

Abstract

Peripheral nerve injury induces long-lasting changes in sensory neurons that contribute to the development of neuropathic pain. Although the histamine H3 receptor (H3R) is best known for regulating neurotransmitter release in the central nervous system, its expression and role in dorsal root ganglia (DRG) remain poorly understood. In this study, we examined the expression, cellular distribution, and functional role of H3 R in DRG and implications in neuropathic pain. Sciatic nerve injury increased membrane-associated H3R protein expression in the DRG, suggesting enhanced receptor trafficking or stabilization at the neuronal membrane. Single-cell transcriptomic analysis revealed that H3R mRNA expression in DRG is predominantly restricted in peptidergic sensory neurons and C-LTMRs neurons. Fluorescence imaging and transcriptomic analysis also suggest that the majority of H3R co-express with TrkA (a NGF receptor) sensory neuron populations. These findings identify a subset of NGF-responsive nociceptors in which H3R may directly influence injury-induced sensitization. Pain behavior assessment demonstrated a paradoxical role of an H3R inverse agonist (GSK334429), which reduces mechanical hypersensitivity caused by chronic constriction injury (CCI) with no change in thermal pain. Patch-clamp recordings show that the GSK334429 attenuates NGF-induced hyperexcitability in DRG neuronal cultures. Overall, our work suggests a contributing role of H3R in modality-specific effects on sensory processing through its enrichment in specific neuronal populations in DRG.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Kumar, A., Kumar, R., Kumari, P., Bagade, A., Yadav, A., Kumar, B. A., Dogra, S., Umrao, D., Copits, B. A., Zorumski, C. F., Mennerick, S., Yadav, P. N.. 2026-09-03. Targeting Histamine H3 Receptors to Suppress NGF-Driven Hyperexcitability in Neuropathic Pain. https://doi.org/10.64898/2026.08.28.746833

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗