Neuropathic pain; what we know and what we should do about it

Frontiers in Pain Research, Год журнала: 2023, Номер 4

Опубликована: Сен. 22, 2023

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve promotes Schwann cell activation and invasion immunocompetent cells into site injury, spinal cord higher sensory structures such as thalamus cingulate cortices. Various cytokines, chemokines, growth factors, monoamines neuropeptides effect two-way signalling between neurons, glia immune cells. This sustained hyperexcitability spontaneous activity in primary afferents that crucial for onset persistence well misprocessing information supraspinal structures. Much current understanding aetiology identification drug targets derives studies consequences peripheral rodent models. Although a vast amount has been forthcoming, translation this clinical arena minimal. Few, if any, major therapeutic approaches have appeared since mid 1990's. may reflect failure recognise differences processing males vs. females, cellular responses different types humans animals. Basic science which seek bridge knowledge gap include better assessment animal models, use models emulate human disease, stratification phenotypes according quantitative signs symptoms disease. lead more personalized effective treatments individual patients. Significance statement: There an urgent need find new neuropathic pain. classical revealed essential features central sensitization some molecular mechanisms involved, they do not adequately model multiplicity states injuries bring forth clinic. review seeks integrate disciplines understand pain; including immunology, biology, electrophysiology biophysics, anatomy, neurology, pharmacology behavioral science. Beyond this, it underlines ongoing refinements basic practice will engender improved management.

Язык: Английский

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Targeted ubiquitination of NaV1.8 reduces sensory neuronal excitability

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 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.

Язык: Английский

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Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 13, 2023

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools transgenic models for gaining long-term genetic access MOR+ neural types circuits involved in modulating pain, analgesia addiction across species are limited. To address this, we developed catalog MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression cells. MORp designed from regions upstream mouse Oprm1 gene (mMORp) were validated transduction efficiency selectivity endogenous neurons brain, spinal cord, periphery mice, with additional studies revealing robust rats, shrews, human induced pluripotent stem (iPSC)-derived nociceptors. The mMORp vivo fiber photometry, behavioral chemogenetics, intersectional strategies also demonstrated. Lastly, (hMORp) efficiently transduced macaque cortical OPRM1+ Together, our toolkit provides researchers type functionally mu-opioidergic range vertebrate translational addiction, neuropsychiatric disorders.

Язык: Английский

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Gene therapy for chronic pain management

Cell Reports Medicine, Год журнала: 2024, Номер unknown, С. 101756 - 101756

Опубликована: Окт. 1, 2024

Язык: Английский

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Facilitation of Ca_V3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract The Ca V 3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability nociceptive neurons; endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover novel peptide albumin (1-26) facilitates channel gating by chelating trace metals tonically inhibit via H191 residue. Importantly, also potently modulated T-currents human rodent dorsal root ganglion (DRG) neurons. In vivo pain studies revealed injections resulted robust mechanical heat hypersensitivity. This hypersensitivity was abolished with T-channel inhibitor, null mice H191Q knock-in mice. discovery chelators deepens our understanding neuronal hyperexcitability may facilitate design analgesics unique mechanisms action.

Язык: Английский

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The Persistent Pain Enigma: Molecular Drivers Behind Acute-to-Chronic Transition

Neuroscience & Biobehavioral Reviews, Год журнала: 2025, Номер 173, С. 106162 - 106162

Опубликована: Апрель 14, 2025

Язык: Английский

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Mimicking opioid analgesia in cortical pain circuits

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 29, 2024

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous exogenous opioid signaling within mitigate cortical nociception, reducing unpleasantness. However, specific functional molecular identities cells mediating analgesia remain elusive. Given complexity as sensory emotional experience, richness ethological pain-related behaviors, we developed standardized, deep-learning platform for deconstructing behavior dynamics associated with component mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias quantification accelerated analysis from weeks to hours, which leveraged discover that morphine altered attentional motivational behaviors akin humans. Through activity-dependent genetics single-nuclei RNA sequencing, identified ensembles nociceptive neuron-types expressing mu-opioid receptors. Tuning receptor expression these bidirectionally modulated analgesia. Moreover, employed synthetic promoter-driven approach cell-type optical chemical genetic viral therapies mimic morphine's pain-relieving effects cingulate, without reinforcement. This offers novel strategy precision management by targeting key circuit on-demand, non-addictive, effective

Язык: Английский

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Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Май 9, 2024

This study reports that targeting intrinsically disordered regions of NaV1.7 protein facilitates discovery sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition INa1.7, INa1.6, INa1.3, and INa1.1. but not INa1.5 INa1.8 was found a prototype, named NaViPA1, which derived from the intracellular loop 1 is conserved among TTXs NaV subtypes. NaViPA1 expression in primary neurons (PSNs) dorsal root ganglia (DRG) produced significant INa TTXr INa. DRG injection AAV6-encoded significantly attenuated evoked spontaneous pain behaviors both male female rats with neuropathic induced by tibial nerve injury (TNI). Whole-cell current clamp PSNs showed normalized PSN excitability TNI rats, suggesting reversal injury-induced neuronal hypersensitivity. Immunohistochemistry revealed efficient restricted their central peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition channels replicated human iPSC-derived neurons. These results summate promising analgesic lead that, combined AAV-mediated PSN-specific block multiple NaVs, has potential as nerve-restricted therapeutics.

Язык: Английский

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Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates

Brain Structure and Function, Год журнала: 2023, Номер 229(1), С. 1 - 14

Опубликована: Ноя. 24, 2023

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through variety dysfunctions related to the extent damage and at different anatomical locations. Despite extensive research, it remains unclear why some are especially susceptible disease, while others affected less or even spared. In this article, we review neurobiological mechanisms, neurochemical profiles, morpho-functional characteristics various neuron groups types units implicated in their differential exposure degeneration. We discuss specific cell-autonomous (intrinsic) extrinsic factors influencing vulnerability gradient ALS, with impact on manifestation, course, prognosis, as revealed preclinical clinical studies. consider outstanding challenges emerging opportunities for interpreting phenotypic mechanistic variability identify targets interventions.

Язык: Английский

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Trim14-IκBα Signaling Regulates Chronic Inflammatory Pain in Rats and Osteoarthritis Patients

Neuroscience, Год журнала: 2024, Номер 548, С. 39 - 49

Опубликована: Май 1, 2024

Chronic inflammatory pain is the highest priority for people with osteoarthritis when seeking medical attention. Despite availability of NSAIDs and glucocorticoids, central sensitization peripheral make increasingly difficult to control. Previous studies have identified ubiquitination system as an important role in chronic pain. Our study displayed that E3 ubiquitin ligase tripartite motif-containing 14 (Trim14) was abnormally elevated serum patients pain, degree positively correlated Trim14 elevation. Furthermore, CFA-induced rat model showed significantly increased L3-5 spinal dorsal horn (SDH) root ganglion (DRG), turn inhibitor nuclear factor Kappa-B isoform α (IκBα) decreased after After intrathecal injection siRNA inhibit expression, IκBα expression reversed increased, behaviors anxiety rats were relieved. Overall, these findings suggested may contribute by degrading IκBα, become a novel therapeutic target

Язык: Английский

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