Quantifying the contribution of somatosensory afferent types and changes therein to pain sensitivity using transcutaneous optogenetic stimulation in behaving mice DOI Creative Commons
Yu‐Feng Xie, Christopher Dedek, Steven A. Prescott

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

ABSTRACT Optogenetics provides an unprecedented opportunity to delineate how different somatosensory afferents contribute sensation, including pain. By expressing channelrhodopsin-2 (ChR2) in certain afferents, those can be selectively activated by transcutaneous photostimuli applied behaving mice. Despite the great care taken precisely target expression of ChR2, imprecise photostimulation has hindered quantitative behavioral testing. Here, using a robot reproducibly photostimulate mice and measure their paw withdrawal, we show that activating nociceptors with ramped evokes faster withdrawal than co-activating nociceptive non-nociceptive consistent gate control. We also inflammation-induced hyperexcitability is sufficient increase pain sensitivity. Electrophysiological testing confirmed inflammation increases nociceptor excitability without affecting phototransduction. Data further suggest latency depends on number rather strongly each activated. Consistent changes described somata, consequences peripherally blocking voltage-gated sodium (Na V ) channels showed axons normally rely Na 1.8 but upregulate 1.7 after inflammation, important clinical implications for drug efficacy. Collectively, these results demonstrate utility optogenetic when delivered strategically designed are used. SIGNIFICANCE STATEMENT Transcutaneous stimulation was first explore neural basis over decade ago. control which express actuators, sensitivity such been crude methods response measurement. highly robotic detection. comparing equivalent activation antinociceptive effect latter input. increased due associated change isoform expression. from reflects many recruited.

Language: Английский

Pathology of pain and its implications for therapeutic interventions DOI Creative Commons
Bo Cao,

Qixuan Xu,

Yajiao Shi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 8, 2024

Abstract Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management crucial for individuals suffering from pain. However, current methods assessment treatment fall short clinical needs. Benefiting advances in neuroscience biotechnology, neuronal circuits molecular mechanisms critically involved modulation have been elucidated. These research achievements incited progress identifying new diagnostic therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting stage subsequent contents. The review next delves into underlying disorders, including gene mutation, epigenetic modification, posttranslational inflammasome, signaling pathways microbiota. To better present a comprehensive view research, two prominent issues, sexual dimorphism comorbidities, are discussed detail based on findings. status quo evaluation manipulation summarized. A series improved innovative strategies, such as therapy, monoclonal antibody, brain-computer interface microbial intervention, making strides towards application. We highlight existing limitations future directions enhancing quality preclinical research. Efforts decipher complexities pathology will be instrumental translating scientific discoveries practice, thereby improving bench bedside.

Language: Английский

Citations

27
Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids DOI Creative Commons
Mohammad‐Reza Ghovanloo, Sidharth Tyagi, Peng Zhao

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(4)

Published: Jan. 21, 2025

Pain impacts billions of people worldwide, but treatment options are limited and have a spectrum adverse effects. The search for safe nonaddictive pain treatments has led to focus on key mediators nociceptor excitability. Voltage-gated sodium (Nav) channels in the peripheral nervous system—Nav1.7, Nav1.8, Nav1.9—play crucial roles signaling. Among these, Nav1.8 shown promise due its rapid recovery from inactivation role repetitive firing, with recent clinical studies providing proof-of-principal that block can reduce humans. We report here three nonpsychotomimetic cannabinoids—cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN)—effectively inhibit suggesting their potential as analgesic compounds. In particular, CBG shows significant ability effectively excitability sensory neurons. These findings highlight therapeutic cannabinoids, particularly CBG, agents may attenuate via warranting further vivo studies.

Language: Английский

Citations

3
Targeted ubiquitination of NaV1.8 reduces sensory neuronal excitability DOI Open Access
Sidharth Tyagi, Mohammad‐Reza Ghovanloo, Matthew Alsaloum

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na V 1.8, pivotal driver of signaling, is clinically validated target for the development novel, non-addictive therapeutics. Small molecule inhibitors against 1.8 have shown promise in acute indications, but large clinical effect sizes not yet been demonstrated efficacy chronic indications lacking. An alternative strategy to channels analgesia reduce number that present on nociceptor membranes. We generated therapeutic heterobifunctional protein, named UbiquiNa , contains 1.8-selective binding module catalytic subunit NEDD4 E3 Ubiquitin ligase. show UbiquiNav significantly reduces expression plasma membrane currents rodent sensory neurons. demonstrate selective over other isoforms components neuronal electrogenisome. then normalizes distribution protein distal axons, hyperexcitability vitro models inflammatory chemotherapy-induced neuropathic pain. Our results serve as blueprint design therapeutics leverage ubiquitination analgesia.

Language: Английский

Citations

1
Unveiling the Mechanisms of Pain in Endometriosis: Comprehensive Analysis of Inflammatory Sensitization and Therapeutic Potential DOI Open Access

Yixiao Chen,

Tian Li

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1770 - 1770

Published: Feb. 19, 2025

Endometriosis is a complicated, estrogen-dependent gynecological condition with high morbidity rate. Pain, as the most common clinical symptom of endometriosis, severely affects women's physical and mental health exacerbates socioeconomic burden. However, specific mechanisms behind occurrence endometriosis-related pain remain unclear. It currently believed that endometriosis related to various factors, such immune abnormalities, endocrine disorders, brain-gut axis, angiogenesis, mechanical stimulation. These factors induce systemic chronic inflammation, which stimulates nerves subsequently alters neural plasticity, leading nociceptive sensitization thereby causing pain. In this paper, we compile review articles published on study mechanisms. Starting from influencing associated explain relationship between these inflammation further elaborate potential by induces sensitization. We aim reveal possible pain, well sensitization, offer new targets for treatment

Language: Английский

Citations

1
Profiling local translatomes and RNA binding proteins of somatosensory neurons reveals specializations of individual axons DOI Open Access
Elizabeth S. Silagi,

E.U. Nduka,

Maria F. Pazyra‐Murphy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

SUMMARY Individual neurons have one or more axons that often extend long distances and traverse multiple microenvironments. However, it is not known how the composition of individual established locally modulated to enable neuronal function plasticity. Here, we use spatial translatomics identify local axonal translatomes in anatomically functionally specialized dorsal root ganglia (DRG). DRG central peripheral opposite directions distinct microenvironments somatosensation. Using Translating Ribosome Affinity Purification RNA sequencing, generated a comprehensive resource mRNAs preferentially translated within each axon. Locally proteins include pain receptors, ion channels, translational machinery, which establish electrophysiologic properties regenerative capacities for We RNA-binding associated with sorting transporting related mRNAs. These findings provide resources addressing translation shapes organization enables subcellular neuroplasticity. HIGHLIGHTS Distinct are localized axons. Axonal govern capacity, electrophysiology. The RBP, SFPQ, coordinates mRNA towards somatosensory translatome data can be explored at painseq.shinyapps.io/CompartmentTRAP/.

Language: Английский

Citations

0
Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy DOI Creative Commons
Yugal Goel, Donovan A. Argueta,

Kirk Peterson

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 445 - 445

Published: April 8, 2025

This study investigates the role of p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion (DRG) neurons development and progression chemotherapy-induced peripheral neuropathy (CIPN). research evaluates whether inhibiting MAPK could reduce neuropathic outcomes a transgenic breast cancer mouse model (C3TAg) wild-type mice (FVB/N) treated with cisplatin. Cisplatin treatment stimulated phosphorylation nuclear translocation DRG neurons. Neflamapimod, specific inhibitor alpha (p38α), proven to be safe clinical trials, inhibited neuronal cisplatin-induced vitro vivo. Neflamapimod also reduced oxidative stress, mitochondrial dysfunction, cleaved caspase-3 expression vitro, protecting integrity preventing axonal damage. Functionally, neflamapimod improved mechanical musculoskeletal hyperalgesia, cold sensitivity cisplatin-treated mice, reversing pain neurotoxicity. identifies as critical driver CIPN highlights its potential therapeutic target for CIPN. Targeting offers promising strategy mitigate neurotoxicity hyperalgesia without exacerbating progression, positioning it novel intervention

Language: Английский

Citations

0
Sculpting excitable membranes: voltage-gated ion channel delivery and distribution DOI
Sidharth Tyagi, Grant P. Higerd‐Rusli, Elizabeth J. Akin

et al.

Nature reviews. Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Language: Английский

Citations

0
The Role of TNF-α in Neuropathic Pain: An Immunotherapeutic Perspective DOI Creative Commons
Mario García‐Domínguez

Life, Journal Year: 2025, Volume and Issue: 15(5), P. 785 - 785

Published: May 14, 2025

TNF-α is a pro-inflammatory cytokine that plays pivotal role in the regulation of immune responses. It predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. participates various physiological processes, including proliferation differentiation. Moreover, has been implicated pathogenesis numerous inflammatory autoimmune disorders. Recent studies have highlighted important neuropathic pain, complex frequently disabling condition caused nerve injury or dysfunction. Increased levels nervous system associated with onset contributing neuronal sensitization alterations pain signaling pathways. This study supports idea connects system, thereby supporting our understanding neuroimmune interface bringing potential treatment against pain: targeting TNF-α. Anti-TNF-α antibody administration reduces behaviors neuroinflammation preclinical animal models. Simultaneously, clinical trials are evaluating safety efficacy anti-TNF-α treatments, preliminary results indicating promising outcomes patients experiencing pain. Here, goes beyond conventional spectrum pathologies initiates new mechanism-based approach defining improving quality life individuals affected together an area colossal unmet need.

Language: Английский

Citations

0
Real-time imaging of axonal membrane protein life cycles DOI
Sidharth Tyagi, Grant P. Higerd‐Rusli, Elizabeth J. Akin

et al.

Nature Protocols, Journal Year: 2024, Volume and Issue: 19(9), P. 2771 - 2802

Published: June 3, 2024

Language: Английский

Citations

1
Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders DOI Creative Commons
Sulayman D. Dib‐Hajj, Stephen G. Waxman

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(13)

Published: June 30, 2024

Multiple approaches have targeted voltage-gated sodium (Nav) channels for analgesia. In this issue of the JCI, Shin et al. identified a peptide aptamer, NaViPA1, carrying short polybasic motif flanked by serine residues in structurally disordered region loop 1 tetrodotoxin-sensitive (TTX-S) but not tetrodotoxin-resistant (TTX-R) channels. NaViPA1h inhibited TTX-S NaV and attenuated excitability sensory neurons. Delivery NaViPA1 vivo via adeno-associated virions restricted its expression to peripheral neurons induced analgesia rats. Targeting linear motifs manner may provide gene therapy modality, with minimal side effects due peripherally-restricted biodistribution, which opens up therapeutic strategy hyperexcitability disorders, including pain.

Language: Английский

Citations

1