Biology subjects

Khanna, R.

Publications and source records attributed to Khanna, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Vertical climbing in mice: a translationally relevant measure of pain-related impact on natural behaviour

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.

neuroscience↗

bioRxiv2026

Peripheral NaV1.7 modulation reveals divergent peripheral and central adaptations in persistent trigeminal pain

Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.

neuroscience↗

bioRxiv2026

A mouse model of myotonic dystrophy type 1 exhibits pain-like behavior and peripheral nociceptor hyperexcitability

Pain is a prevalent and disabling symptom of myotonic dystrophy type 1 (DM1), yet its underlying mechanisms remain poorly understood. Using HSA LR20b transgenic mice, we found multimodal mechanical and thermal hypersensitivity. Whole-cell electrophysiological recordings demonstrated depolarized resting membrane potentials and increased action potential firing selectively in small- and medium-diameter dorsal root ganglion neurons. These findings identify peripheral nociceptor sensitization as a potential mechanism contributing to pain in DM1.

neuroscience↗

bioRxiv2026

The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress

Stress granules form in response to diverse cellular perturbations to sequester translation components until the stress is resolved. Stress granules are composed of RNA-protein assemblies in membrane delimited structures and must be rapidly disassembled to release components to allow translation to resume. Disassembly of stress granules formed in response to heat stress is dependent on ubiquitiylation of stress granule components such as G3BP1. Ubiquitylation of stress granule proteins recruits the AAA-ATPase p97 (also known as VCP) to enable ubiquitin-dependent disassembly of these structures. Loss of p97 activity leads to the persistence of stress granules and is implicated in several age-related neurodegenerative diseases. Here we show that p97 recruitment to stress granules is dependent on its ubiquitin binding co-factor p47. p47 translocates to stress granules in response to a variety of cellular stressors and is required for the recruitment of p97 to stress granules. Loss of p47 leads to an inhibition in stress granule disassembly. We further show that p47 associates with G3BP1 in response to heat stress in a ubiquitin-dependent manner. Taken together our data adds to the growing list of p97 adaptors that are implicated in the recruitment of p97 for dissolution of stress granules.

cell biology↗

bioRxiv2026

An autoinhibitory regulatory switch governs heterotypic phase separation and liquid-to-solid phase transition of TDP-43 and tau into cytotoxic amyloids

Biomolecular condensates formed via macromolecular phase separation of proteins and nucleic acids control a myriad of essential cellular processes, whereas abnormal phase transitions into solid-like aggregates are associated with a range of fatal neurodegenerative diseases. Here, we present a unique case to demonstrate that two neuronal proteins, TDP-43 and tau, undergo heterotypic phase separation via domain-specific interactions regulated by an autoinhibitory conformational switch. Using single-molecule FRET (Forster resonance energy transfer), in combination with multi-color high-resolution imaging, fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, single-droplet fluorescence anisotropy imaging, homoFRET microscopy, fluorescence lifetime-FRET imaging, vibrational Raman spectroscopy, and electron microscopy, we unmask the interplay of molecular drivers and dissect the sequence of events associated with the formation of TDP-43:tau co-condensates that undergo liquid-to-solid phase transitions into cytotoxic amyloids. Our cellular studies show that a disease-associated cytosolic fragment of TDP-43 recruits tau into oxidative stress-induced cytoplasmic granules, eliciting cellular toxicity. Our findings provide mechanistic underpinnings of co-condensation-mediated aberrant phase transitions associated with exacerbated neuropathological outcomes.

biophysics↗

bioRxiv2026

NRP1 regulates basal nociception: characterization of a peptidergic-specific NRP1 knockout mouse

Neuropilin-1 (NRP1) is a single pass transmembrane glycoprotein that can form a receptor complex with several tyrosine kinase receptors, including the vascular endothelial growth factor (VEGF) receptor. Previous studies have reported that binding of VEGFA to this receptor complex elicits mechanical allodynia and thermal hyperalgesia through potentiation of voltage-gated sodium and calcium channel activity. We find that Nrp1 mRNA and protein is widely distributed in naive mouse and rat DRG neurons, including peptidergic afferents. A CGRPcreER: NRP1fl/fl transgenic mice was generated to investigate the role of peptidergic NRP1 in basal nociception. Following in vivo loss of NRP1, while mice are hyposensitive to both noxious heat and mechanical stimuli. Under normal conditions, VEGFA elicits mechanical hypersensitivity, an effect that was absent in our NRP1 knockout mouse. Furthermore, VEGFA induced neuronal hyperexcitability was lost in CGRP expressing neurons isolated from this NRP1 knockout mouse. This study validates the NRP1 knockout mouse and confirms previous findings that VEGFA, often released during pathological pain conditions, requires peptidergic NRP1. Interestingly, we find that in the absence of ongoing injury or inflammation, peptidergic NRP1 regulates basal nociception and pain-like behaviors.

neuroscience↗

bioRxiv2025

Enabling wider access to human molecular neuroscience research in pain: A simple preservation method for human dorsal root ganglion neurons in Hibernate A media

The use of human dorsal root ganglion (DRG) from organ donors opens the door for research into the molecular biology and physiology of human nociceptors; however, there are barriers to working with this tissue including logistical difficulties and limited access. We present an approach using Hibernate media to temporarily store either whole DRGs or dissociated DRG neurons prior to culturing and functional testing. Dissociation of DRGs following temporary storage (4-16hrs) in Hibernate media resulted in similar neuronal and immune cell yield as acutely dissociated DRGs. Neurons derived from DRGs stored in Hibernate media prior to dissociation exhibited similar electrophysiological properties and capsaicin responses as acutely dissociated DRG neurons. Similarly, neurons from acutely dissociated DRGs stored in Hibernate media (>24hrs) and shipped to geographically distant laboratories produced neuronal cultures displaying comparable electrophysiological properties as acutely cultured neurons. This approach overcomes insurmountable logistical burdens and increases access to freshly recovered human DRGs.

neuroscience↗

bioRxiv2025

Inverse-scattering in biological samples via beam-propagation

Multiple scattering limits optical imaging in thick biological samples by scrambling sample-specific information. Physics-based inverse-scattering methods aim to computationally recover this information, often using non-convex optimization to reconstruct the scatter-corrected sample. However, this non-convexity can lead to inaccurate reconstructions, especially in highly scattering samples. Here, we show that various implementation strategies for even the same inverse-scattering method significantly affect reconstruction quality. We demonstrate this using multi-slice beam propagation (MSBP), a relatively simple nonconvex inverse-scattering method that reconstructs a scattering samples 3D refractive-index (RI). By systematically conducting MSBP-based inverse-scattering on both phantoms and biological samples, we showed that an amplitude-only cost function in the inverse-solver, combined with angular and defocus diversity in the scattering measurements, enabled high-quality, fully-volumetric RI imaging. This approach achieved subcellular resolution and label-free 3D contrast across diverse, multiple-scattering samples. These results lay the groundwork for robust use of inverse-scattering techniques to achieve biologically interpretable 3D imaging in increasingly thick, multicellular samples, introducing a new paradigm for deep-tissue computational imaging.

bioengineering↗

bioRxiv2025

OrganoidChip+: a Microfluidic Platform for Culturing, Staining, Immobilization, and High-Content Imaging of Adult Stem Cell-Derived Organoids

High-content imaging (HCI) and analysis are the keys for advancing our understanding of the science behind organogenesis. To this end, culturing adult stem cell-derived organoids (ASOs) in a platform that also enables live imaging, staining, immobilization, and fast high-resolution imaging is crucial. However, existing platforms only partially satisfy these requirements. In this study, we present the OrganoidChip+, an all-in-one microfluidic device designed to integrate both culturing and HCI of ASOs all within one platform. We previously developed the OrganoidChip as a robust imaging tool. Now, the OrganoidChip+ incorporates several additional features for culturing organoids in addition to fluorescence staining and imaging without the need for sample transfer. The organoids grown within a culture chamber are stained and then transferred to immobilization chambers for blur-free, high-resolution imaging at predetermined locations. We cultured adult stem cell-derived intestinal organoids in the chip for 7 days and tracked growth rates of each organoid using intermittent brightfield images, followed by multiple image-based assays, including viability assay using widefield fluorescence imaging, a redox ratio assay using label-free, two-color, two-photon microscopy, and immunofluorescence assays using confocal microscopy. These assays serve as proof-of-concept to showcase the chips capabilities in HCI of ASOs. Organoids cultured in the chip exhibited superior average growth rates over those in traditional Matrigel dome cultures, off-chip. Viability and redox ratio measurements of on-chip organoids were comparable or slightly better than their off-chip counterparts. Confocal imaging further confirmed that the OrganoidChip+ supports robust organoid culture while enabling detailed, high-resolution analysis. This all-in-one platform holds great potential for advancing ASO-based research, offering a scalable and cost-effective solution for HCI and analysis in organogenesis, drug screening, and disease modeling.

bioengineering↗

bioRxiv2025

Parabrachial bombesin receptor subtype 3 neurons facilitate heat pain in persistent inflammation

The parabrachial nucleus (PBN) is a critical hub for pain processing that acts as a switchboard for nociceptive signals, relaying sensory information to forebrain regions that integrate the sensory and affective dimensions of pain. Although the PBN is well established as a key regulator of pain, the remarkable heterogeneity of its neuronal populations has hindered efforts to identify specific cell types responsible for distinct aspects of pain processing. Here, we identify bombesin receptor subtype 3 (Brs3)-expressing neurons as a distinct glutamatergic PBN subpopulation involved in heat hypersensitivity associated with persistent pain. Using Fos expression analysis and in vivo calcium imaging, we demonstrate that Brs3 neurons exhibit heightened activity in response to heat stimulation following an inflammatory insult or neuropathic injury. Inhibition of Brs3 neurons effectively reduces heat, but not mechanical, hypersensitivity induced by both inflammatory and neuropathic pain, suggesting a specific role in processing heat hypersensitivity. Ablation of parabrachial Brs3 neurons prior to induction of pain also selectively prevents the development of heat hypersensitivity induced by persistent inflammation in mice. Brs3-expressing neurons encompass multiple previously identified pain-related PBN subpopulations, including those expressing the mu opioid receptor (Oprm1), tachykinin 1 receptor (Tacr1), and neuropeptide Y Y1 receptor (Npy1r), positioning Brs3 as a potential unifying marker of heat hypersensitivity circuits. These findings provide new insight into the organization of pain-processing networks in the PBN and highlight Brs3 neurons as a crucial population for heat pain.

neuroscience↗

bioRxiv2024

A synthetic potassium channel reduces oxidative stress 1 via cellular adaptronics

Aerobic metabolism is crucial for human life but reactive oxygen species (ROS) byproducts cause cellular toxicity. Although antioxidant defenses usually maintain ROS levels within a safe range, ROS production can exceed the buffering capacity of cells, causing oxidative stress and disease. Inspired by the principle of adaptronics, we created a synthetic potassium channel that senses cellular ROS levels and mitigates oxidative stress by modulating membrane potential. Engineered from TASK1 channel, ROSTASK1 is sensitive to supraphysiological ROS levels, imposing restorative membrane potential changes on cells or organelles under oxidative stress. We also engineered a blue-light sensitive ROSTASK1 to achieve optogenetic control. In proof-of-concept experiments, mitochondrially-delivered ROSTASK1 rescued ROS overproduction in myoblasts from a Leigh syndrome patient and ROSTASK1 abolished chronic pain-like behavior in mouse models of inflammation and nerve injury. Thus, by functioning as both a sensor and modulator of ROS levels, ROSTASK1 provides a self-healing system during oxidative stress.

biophysics↗

bioRxiv2024

DNA methylation and demethylation driven regulation of sepsis

During dysregulated inflammation and sepsis, there is a sudden surge of cytokines, such as TNF alpha, IL6, and IL10, which disrupts the body homeostasis. This sudden and rapid increase in cytokine gene expression cannot be explained by the conventional central dogma mechanism. DNA methylation is one of the most significant epigenetic modifications. DNA methylation is mostly associated with the suppression of gene activity, and DNA demethylation is associated with the activation of gene activity. There are numerous transcription factors, such as CREB1, c-FOS, AP-1, IRF1, and EGR1, that play pivotal roles in regulating inflammation. Thus, it was hypothesized that changes in the DNA methylation patterns of cytokine promoter regions or in the promoter regions of these specific transcription factors might be the potential reasons for the increase in cytokine levels during sepsis. During endotoxin stimulation, DNA methyltransferases were suppressed, and DNA methylation levels were altered at the global level. Bisulfite sequencing revealed no change in the DNA methylation patterns of the TNF-alpha, IL6 and IL10 cytokine promoters. The CREB1 and c-FOS transcription factor promoters were demethylated after LPS stimulation and in clinical sepsis samples. Overall, this study highlights the importance of the role of DNA methylation in sepsis.

molecular biology↗

bioRxiv2024

Identifying interactions between TDP-43 N-terminal and RNA binding domains

TAR DNA-binding Protein 43 (TDP-43) plays a crucial role in the pathophysiology and progression of Amyotrophic Lateral Sclerosis (ALS), affecting both familial and sporadic cases. TDP-43 is an intrinsically disordered multidomain protein that consists of an N-terminal domain (NTD1-102), two tandem RNA recognition motifs (RRM1102-177 and RRM2191-260), and an intrinsically disordered glycine-rich C-terminal261-414 domain. We previously identified a chemical probe which led to allosteric alterations between the RRM and NTD of TDP-43. We attributed these changes to potential interdomain interactions between the NTD and RRM segments. In this work, we compared the 2D [1H,15N] HSQC-NMR resonances of two constructs, TDP-43102-260 (RRM domain alone) against TDP-431-260 (NTD linked to RRM) and observed clustered shifts in the RNA binding sites of both RRM domains. To investigate why these shifts appeared in the RRM domains, in the absence of RNA, we hypothesized that the NTD domain could be stacking on the RRM domains. Thus, we modeled NTD-RRM interactions using protein-protein docking along with de novo sequence-to-structure predictions of TDP-431-260 that propose NTD stacking onto the RRM domains. Using Carr-Purcell-Meiboom-Gill (CPMG)-relaxation dispersion NMR spectroscopy, we demonstrated evidence of an interaction between NTD1-102 and RRMs102-260. Finally, we investigated the impact of NTD on RNA binding using 2D 15N-HSQC-NMR and microscale thermophoresis (MST) by titration of a short UG-rich RNA sequence and observed significant changes in RNA binding between TDP-43102-260 and TDP-431-260, further suggesting the NTD plays a role in TDP-43 RNA interactions.

biophysics↗

bioRxiv2024

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors

Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

neuroscience↗

bioRxiv2024

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart

BackgroundMetabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. MethodsWe utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. ResultsHere, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. ConclusionsThis study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

molecular biology↗

bioRxiv2024

Chaperone-mediated heterotypic phase separation regulates liquid-to-solid phase transitions into amyloid fibrils

Biomolecular condensates formed via the phase separation of proteins and nucleic acids are thought to regulate a myriad of cellular processes with exquisite spatiotemporal precision. However, such highly dynamic, viscoelastic, mesoscopic, intracellular membraneless bodies can undergo aberrant liquid-to-solid transitions into a range of amyloid-like species. The formation of such pathological assemblies necessitates their clearance by the cellular protein quality control machinery comprising molecular chaperones. Nonetheless, the mechanism underlying the chaperone-mediated regulation of protein homeostasis within biomolecular condensates remains elusive. Here, we present a unique case demonstrating that a heat shock protein 40 (Hsp40), Ydj1, promotes the heterotypic phase separation of intrinsically disordered tau via intermolecular electrostatic and hydrophobic interactions. Through a diverse array of tools involving high-resolution fluorescence imaging, single-droplet steady-state and picosecond time-resolved fluorescence anisotropy, and single-molecule FRET (Forster resonance energy transfer), we elucidate the diverse structural conformations of tau present within phase-separated heterotypic condensates that are otherwise predisposed to aggregation. Our vibrational Raman spectroscopy and electron microscopy data show that the presence of Ydj1 in tau-Ydj1 condensates abolishes the formation of amyloid fibrils, unlike tau-only droplets. By sequentially deleting segments, we identify amyloidogenic hexapeptide motifs located in the hydrophobic microtubule-binding region of tau that foster contacts with the peptide-binding regions of Ydj1, promoting the formation of tau-Ydj1 binary condensates. Additionally, we show that the underlying network of interactions governing these condensates can be further tuned by RNA. Our results underscore an intriguing interplay of molecular drivers that govern chaperone-associated phase separation, with broader implications for the chaperoning of a wide range of intrinsically disordered proteins involved in physiology and disease.

biophysics↗

bioRxiv2024

Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.

neuroscience↗

bioRxiv2024

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

neuroscience↗