A novel approach to completely alleviate peripheral neuropathic pain in human patients: insights from preclinical data

Frontiers in Neuroanatomy, Journal Year: 2025, Volume and Issue: 18

Published: Jan. 7, 2025

Neuropathic pain is a pervasive health concern worldwide, posing significant challenges to both clinicians and neuroscientists. While acute serves as warning signal for potential tissue damage, neuropathic represents chronic pathological condition resulting from injury or disease affecting sensory pathways of the nervous system. characterized by long-lasting ipsilateral hyperalgesia (increased sensitivity pain), allodynia (pain sensation in response stimuli that are not normally painful), spontaneous unprovoked pain. Current treatments generally inadequate, prevention remains elusive. In this review, we provide an overview current treatments, their limitations, discussion on capsaicin its analog, resiniferatoxin (RTX), complete alleviation nerve injury-induced animal model where fifth lumbar (L5) spinal unilaterally ligated cut, hyperalgesia, allodynia, akin human The application RTX adjacent uninjured L3 L4 nerves completely alleviated prevented mechanical thermal following L5 injury. effects treatment were specific unmyelinated fibers (responsible sensation), while thick myelinated touch mechanoreceptor sensations) remained intact. Here, propose translate these promising preclinical results into effective therapeutic interventions humans direct patients who suffer due peripheral injury, surgical interventions, diabetic neuropathy, trauma, vertebral disc herniation, entrapment, ischemia, postherpetic lesion, cord

Language: Английский

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Identifying behavior regulatory leverage over mental disorders transcriptomic network hubs toward lifestyle-dependent psychiatric drugs repurposing

Human Genomics, Journal Year: 2025, Volume and Issue: 19(1)

Published: March 19, 2025

Abstract Background There is a vast prevalence of mental disorders, but patient responses to psychiatric medication fluctuate. As food choices and daily habits play fundamental role in this fluctuation, integrating machine learning with network medicine can provide valuable insights into disease systems the regulatory leverage lifestyle health. Methods This study analyzed coexpression modules MDD PTSD blood transcriptomic profile using modularity optimization method, first runner-up Disease Module Identification DREAM challenge . The top genes both were detected random forest model. Afterward, signature two predominant habitual phenotypes, diet-induced obesity smoking, identified. These transcription/translation regulating factors ( TRFs ) signals transduced toward disorders’ genes. A bipartite drugs that target TRFS together or hubs was constructed. Results research revealed one hub, CENPJ, which known influence intellectual ability. observation paves way for additional investigations potential CENPJ as novel therapeutic agents development. Additionally, most predicted associated multiple carcinomas, notable SHCBP1. SHCBP1 risk factor glioma, suggesting importance continuous monitoring patients mitigate cancer comorbidities. signaling illustrated three biomarkers co-regulated by phenotype TRFs. 6-Prenylnaringenin Aflibercept identified candidates targeting hubs: ATP6V0A1 PIGF. However, have no over Conclusion Combining biology succeeded revealing notoriously spreading PTSD. approach offers non-invasive diagnostic pipeline identifies drug targets could be repurposed under further investigation. findings contribute our understanding complex interplay between habits, interventions, thereby facilitating more targeted personalized treatment strategies.

Language: Английский

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Sulfide and polysulfide as pronociceptive mediators: Focus on Cav3.2 function enhancement and TRPA1 activation

Journal of Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 155(3), P. 113 - 120

Published: May 3, 2024

Reactive sulfur species including sulfides, polysulfides and cysteine hydropersulfide play extensive roles in health disease, which involve modification of protein functions through the interaction with metals bound to proteins, cleavage disulfide (S-S) bonds S-persulfidation residues. Sulfides over a wide micromolar concentration range enhance activity Cav3.2 T-type Ca2+ channels by eliminating Zn2+ channels, thereby promoting somatic visceral pain. is under inhibition physiological conditions, so that sulfides function reboot from increase excitability nociceptors. On other hand, generated activate TRPA1 via S-persulfidation, facilitating somatic, but not visceral, Thus, enhancement activation polysulfides, synergistically accelerate pain signals. The increased sulfide/Cav3.2 system, particular, appears have great impact on pathological pain, may thus serve as therapeutic target for treatment neuropathic inflammatory

Language: Английский

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Contribution of T‐type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin‐treated mice of both sexes

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Background and Purpose The chemotherapy agent oxaliplatin can give rise to oxaliplatin‐induced peripheral neuropathy (OIPN). Here, we investigated whether T‐type calcium channels (Ca v 3) contribute OIPN. Experimental Approach We chronically treated mice with assessed pain responses changes in expression of Ca 3.2 channels. also tested the effects channel blockers on cold sensitivity wild‐type null mice. Key Results Oxaliplatin treatment led mechanical hypersensitivity male female Mechanical persisted both sexes. Intraperitoneal or intrathecal delivery pan inhibitors attenuated but not Remarkably occurred even without treatment. Unexpectedly, intrathecal, intraplantar intraperitoneal Z944 TTA‐P2 transiently induced Acute knockdown specific 3 isoforms revealed that depletion 3.1 males either females triggered hypersensitivity. Finally, reducing by disrupting interactions between deubiquitinase USP5 small organic molecule II‐2 reversed importantly did trigger allodynia. Conclusion Implications Altogether, our data indicate differentially regulation hypersensitivity, raise possibility could promote

Language: Английский

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Kurarinone, a Lavandulyl Flavanone from Sophora flavescens, Inhibits T-type Calcium Channels and Exerts Analgesic Effects in a Mouse Model of Inflammatory Pain

ACS Food Science & Technology, Journal Year: 2024, Volume and Issue: 4(10), P. 2355 - 2364

Published: Oct. 8, 2024

Kurarinone, the major lavandulyl flavanone identified in roots of Sophora flavescens, has been reported to have different channel and transporter activity modulation capacities; nevertheless, its ability block T-type channels inflammatory pain not fully investigated. In this work, we used whole-cell patch clamp technique examine kurarinone calcium channels. Kurarinone acted as a nonselective antagonist that inhibited Cav3.2 expressed tsA-201 cells with an IC50 1.1 ± 0.3 μM blocked native mouse dorsal root ganglion neurons. Transiently Cav2.2 were also blocked. Molecular docking analysis predicted phenyl ring, lavandulyl, hydroxyl groups interact directly pore domains all three via hydrogen hydrophobic interactions. administered intraperitoneally (10 mg/kg/i.p.) significantly phase II formalin-induced nocifensive responses mice. Furthermore, reduced thermal hyperalgesia mechanical hypersensitivity mice injected Complete Freund's adjuvant (CFA) into hind paw model. Taken together, our findings indicate analgesic through blocking

Language: Английский

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CaV3.2 T-type calcium channels contribute to CGRP- induced allodynia in a rodent model of experimental migraine

The Journal of Headache and Pain, Journal Year: 2024, Volume and Issue: 25(1)

Published: Dec. 18, 2024

Migraine is a painful neurological syndrome characterized by attacks of throbbing headache, moderate to severe intensity, which associated with photo- and phono- sensitivity as well nausea vomiting. It affects about 15% the world's population being 2–3 times more prevalent in females. The calcitonin gene-related peptide (CGRP) key mediator pathophysiology migraine, significant advance field has been development anti-CGRP therapies. trigeminal ganglion (TG) thought be an important site action for these drugs. Moreover, experimental migraine can induced CGRP injection TG. signaling pathway TG not fully understood, but studies suggest that voltage-gated calcium channels contribute effects relevant migraine. We hypothesised enhances CaV3.2 T-type channel currents periorbital mechanical allodynia. A Co-Immunoprecipitation assay tsA-201 cells revealed form complex RAMP-1, component receptor. Constitutive CGRPR activity was able inhibit induce depolarizing shift both activation inactivation curves. Incubation neurons increased current density ~ 3.6 fold, effect observed from knockout mice. Z944, pan blocker, resulted approximately 80% inhibition currents. In vivo, this treatment abolished allodynia male female Likewise, mice did develop after intraganglionic injection. Finally, we demonstrated depends on its canonical GPCR, followed protein kinase activation. present study suggests modulates TG, possibly mediated receptor PKA increase may represent contributing factor initiation maintenance headache pain during

Language: Английский

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Functional expression and sex dimorphism of the T-type Cav3.2 Calcium Channel in human DRG Neurons

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

Published: Dec. 28, 2024

Abstract T-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform primary sensory neurons of dorsal root ganglion (DRG). Its pharmacological inhibition or gene silencing induces analgesia several preclinical models inflammatory neuropathic pain. However, presence Cav3.2, encoded by CACNA1H gene, human DRG remains unresolved. Using RNA in-situ hybridization electrophysiological recordings, we show that DRGs express a subset positive for neurotrophic factor receptor TrkB ( NTRK2 gene). The current exhibits typical biophysical properties, including low concentration nickel Z944, specific T-type channel blocker advanced clinical development. Conversely, ABT-639, inhibitor failed Phase 2 trials relief, does not inhibit currents neurons. Importantly, from female organ donors, supporting sex differences mechanisms humans. These findings underscore potential continued exploration as therapeutic target treatment highlight likely rely on this to modulate their excitability.

Language: Английский

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