TRPC3/6 Channels Mediate Mechanical Pain Hypersensitivity via Enhancement of Nociceptor Excitability and of Spinal Synaptic Transmission

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Сен. 28, 2024

Abstract Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, highly expressed sensory neurons. However, how these mediate hypersensitivity has remained elusive. It is shown that mice human, upregulated DRG spinal dorsal horn under pathological states. Double knockout TRPC3/6 blunts largely by decreasing nociceptor hyperexcitability synaptic potentiation via presynaptic mechanism. In corroboration nociceptor‐specific ablation produces comparable relief. Mechanistic analysis reveals upon peripheral inflammation, primary neurons get recruited released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from terminals, which turn potentiates transmission through eventually results hypersensitivity. Antagonizing relieves human. Thus, nociceptors crucially involved plasticity constitutes a promising therapeutic target against minor side effects.

Язык: Английский

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Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain: an update

Expert Opinion on Therapeutic Targets, Год журнала: 2023, Номер 27(8), С. 665 - 678

Опубликована: Авг. 3, 2023

Introduction Current treatments for chronic pain are inadequate. Here, we provide an update on the new therapeutic strategies that target dorsal root ganglia (DRGs) in peripheral nervous system a better and safer treatment of pain.Areas covered Despite complex nature its underlying mechanisms, do know changes plasticity modality neurons DRGs play pivotal role. DRG heterogenous offer potential targets different interventions. We discuss last advancements these interventions, which include use systemic local administrations, selective nerve drug delivery, gene therapy. In particular, updates further details molecular characterization primary sensory neurons, analgesics entering market, future therapy approaches.Expert opinion promising due to their key role signaling, unique anatomical location, targeted

Язык: Английский

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Ion Channel Genes in Painful Neuropathies

Biomedicines, Год журнала: 2023, Номер 11(10), С. 2680 - 2680

Опубликована: Сен. 29, 2023

Neuropathic pain (NP) is a typical symptom of peripheral nerve disorders, including painful neuropathy. The biological mechanisms that control ion channels are important for many cell activities and also therapeutic targets. Disruption the cellular govern channel activity can contribute to pathophysiology. voltage-gated sodium (VGSC) most researched in terms NP; however, VGSC impairment detected only <20% neuropathy patients. Here, we discuss potential role other involved sensory signaling (transient receptor cation channels), neuronal excitation regulation (potassium involuntary action generation (hyperpolarization-activated cyclic nucleotide-gated thermal (anoctamins), pH modulation (acid sensing neurotransmitter release (calcium channels) related their prospective as targets

Язык: Английский

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Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Июнь 11, 2024

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with ubiquitous distribution in numerous tissues and various functions both neuronal non-neuronal cells. IGF-1 provides trophic support for many neurons of the central peripheral nervous systems. In system (CNS), IGF-1R signaling regulates brain development, increases firing modulates synaptic transmission. IGF-IR are not only expressed CNS but also sensory dorsal root ganglion (DRG) nociceptive that convey pain signals. DRG express variety receptors ion channels essential players excitability, notably ligand-gated cation channel TRPV1 voltage-gated M-type K

Язык: Английский

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Neurotoxin-Derived Optical Probes for Biological and Medical Imaging

Molecular Imaging and Biology, Год журнала: 2023, Номер 25(5), С. 799 - 814

Опубликована: Июль 19, 2023

Abstract The superb specificity and potency of biological toxins targeting various ion channels receptors are major interest for the delivery therapeutics to distinct cell types subcellular compartments. Fused with reporter proteins or labelled fluorophores nanocomposites, animal their detoxified variants also offer expanding opportunities visualisation a range molecular processes functions in preclinical models, as well clinical studies. This article presents state-of-the-art optical probes derived from neurotoxins channels, discussions applications basic translational biomedical research. It describes design production reviews advantages limitations, prospects future improvements. Given advances imaging tools research areas benefiting use probes, described here resources should assist discovery process facilitate high-precision interrogation therapeutic interventions.

Язык: Английский

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Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome

JCI Insight, Год журнала: 2024, Номер 9(4)

Опубликована: Фев. 13, 2024

Genetic modifications leading to pain insensitivity phenotypes, while rare, provide invaluable insights into the molecular biology of and reveal targets for analgesic drugs. Pain typically results from Mendelian loss-of-function mutations in genes expressed nociceptive (pain-sensing) dorsal root ganglion (DRG) neurons that connect body spinal cord. We document a mechanism arising gene overexpression individuals with rare 7q11.23 duplication syndrome (Dup7), who have 3 copies approximately 1.5-megabase Williams (WS) critical region. Based on parental accounts ratings, people Dup7, mainly children this study, are insensitive following serious injury skin, bones, teeth, or viscera. In contrast, diploid siblings (2 WS region) (1 copy) show standard reactions painful events. A converging series human assessments cross-species cell biological transcriptomic studies identified 1 likely candidate region, STX1A, as underlying phenotype. STX1A codes synaptic vesicle fusion protein syntaxin1A. Excess syntaxin1A was demonstrated compromise neuropeptide exocytosis DRG neurons. Taken together, these data indicate producing "genetic analgesia" Dup7 offer previously untargeted routes control.

Язык: Английский

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Pharmacological and Surgical Approaches to Pain

Springer eBooks, Год журнала: 2024, Номер unknown, С. 161 - 186

Опубликована: Янв. 1, 2024

Язык: Английский

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Neurobiological Correlates of Rheumatoid Arthritis and Osteoarthritis: Remodelling and Plasticity of Nociceptive and Autonomic Innervations in Synovial Joints

The Neuroscientist, Год журнала: 2024, Номер unknown

Опубликована: Дек. 12, 2024

Swelling, stiffness, and pain in synovial joints are primary hallmarks of osteoarthritis rheumatoid arthritis. Hyperactivity nociceptors excessive release inflammatory factors mediators play a crucial role, with emerging data suggesting extensive remodelling plasticity joint innervations. Herein, we review structural, functional, molecular alterations sensory autonomic axons wiring arthritic revisit mechanisms implicated the sensitization nociceptors, leading to chronic pain. Sprouting reorganization fibers invasion ectopic branches into surrounding inflamed tissues associated upregulation markers. These changes frequently complemented by phenotypic switch profiles activation silent axons, inferring homeostatic adjustments reprogramming Identifying critical players neurobiological underpinning rewiring is likely elucidate causatives neuroinflammation pain, assisting finding new therapeutic targets opportunities for interventions.

Язык: Английский

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Development of Herpes Simplex Virus-based Vectors for Gene Therapy

Nihon Ika Daigaku Igakkai Zasshi, Год журнала: 2023, Номер 19(3), С. 218 - 223

Опубликована: Авг. 31, 2023

In recent years, gene and cell therapies have become widely accepted as new therapeutic modalities, a number of therapy drugs been approved. Underlying this advance are innovations in delivery tools, especially viral vectors, which no longer simply transfer tools basic research. Since its initial inception, all aspects dramatically improved, including their safety, functionality, production technology. On the other hand, with use clinically, safety efficacy concerns emerged, is now entering phase. Both preclinical clinical data demonstrated that simple overexpression at disease site through transduction by vector not sufficient to ensure efficacy. Maturation field will require more sophisticated systems highly regulated expression precisely introduce these genes into target cells express them appropriate degree time. Herpes simplex virus (HSV)-based vectors extremely safe functional potential meet current challenges therapy. This makes HSV promising vehicles for chapter focus on trends development

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Окт. 5, 2021

Abstract This study reports that targeting intrinsically disordered regions (IDRs) of Na V 1.7 protein facilitated discovery sodium channel inhibitory peptide aptamers (NaviPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition I Na1.7 , Na1.6 and Na1.3 but not Na1.5 Na1.8 was found a prototype, named NaviPA1, which derived from the intracellular loop 1 is conserved among TTXs subtypes. NaviPA1 expression in primary neurons (PSNs) dorsal root ganglia (DRG) produced significant TTXr . 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 s has potential as nerve-restricted therapeutics.

Язык: Английский

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