Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy

Brain, Год журнала: 2024, Номер 147(9), С. 2991 - 2997

Опубликована: Июль 24, 2024

Abstract Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined preclinical models that drive spontaneous activity, none tested directly on spontaneously active human nociceptors. Using cultured DRG recovered during thoracic vertebrectomy surgeries, we showed inhibition mitogen-activated protein kinase interacting (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses sensory are likely nociceptors based size and action potential characteristics associated painful dermatomes within minutes treatment. Tomivosertib treatment also decreased amplitude produced alterations the magnitude after hyperpolarizing currents, suggesting modification Na+ K+ channel as consequence drug Parallel to effects electrophysiology, eFT508 led profound loss eIF4E serine 209 phosphorylation primary neurons, specific substrate MNK, 2 min Our results create compelling case for future testing MNK inhibitors clinical trials pain.

Язык: Английский

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Artemin sensitises mouse (Mus musculus) and naked mole-rat (Heterocephalus glaber) sensory neurons

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

Опубликована: Апрель 16, 2025

Abstract The naked mole-rat (NMR, Heterocephalus glaber ) is a subterranean rodent that exhibits range of unusual physiological traits, including diminished inflammatory pain. For example, nerve growth factor (NGF), key mediator, fails to induce sensitization sensory neurons and thermal hyperalgesia in NMRs. This lack NGF-induced neuronal results from hypofunctional signaling the NGF receptor, tropomyosin receptor kinase A (TrkA). Like NGF-TrkA signaling, neurotrophic artemin, member glial cell line-derived (GDNF) family, implicated mediating pain through its GDNF family α3 (GFRα3), which expressed by subset dorsal root ganglia (DRG) neurons. Here we investigated GFRα3 expression DRG mice NMRs, as well measuring impact artemin on neuron function both species. Using immunohistochemistry, observed similar abundance mouse NMR neurons, high coexpression with transient potential vanilloid 1 (TRPV1) ion channel suggesting these are nociceptors. electrophysiology, induced depolarization resting membrane decreased rheobase species, diminishing degree TRPV1 desensitization multiple capsaicin stimuli. Overall, indicate sensitizes conserved mechanism modulation.

Язык: Английский

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Profiling human iPSC-derived sensory neurons for analgesic drug screening using a multi-electrode array

Cell Reports Methods, Год журнала: 2025, Номер unknown, С. 101051 - 101051

Опубликована: Май 1, 2025

Язык: Английский

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Selective modification of ascending spinal outputs in acute and neuropathic pain states

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

Опубликована: Апрель 9, 2024

Summary Pain hypersensitivity arises from the plasticity of peripheral and spinal somatosensory neurons, which modifies nociceptive input to brain alters pain perception. We utilized chronic calcium imaging dorsal horn neurons determine how representation stimuli in anterolateral tract, principal pathway transmitting signals brain, changes between distinct states. In healthy conditions, we identify stable, narrowly tuned outputs selective for cooling or warming, a neuronal ensemble activated by intense/noxious thermal mechanical stimuli. Induction an acute sensitization with capsaicin selectively transiently retunes output encode low-intensity contrast, nerve injury-induced neuropathic results persistent suppression innocuous coupled activation normally silent population high-threshold neurons. These demonstrate differential modulation specific during

Язык: Английский

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Top-down attention does not modulate mechanical hypersensitivity consecutive to central sensitization: insights from an experimental analysis

Pain, Год журнала: 2024, Номер 165(9), С. 2098 - 2110

Опубликована: Апрель 3, 2024

According to the neurocognitive model of attention pain, when attentional resources invested in a task unrelated pain are high, limited cognitive can be directed toward pain. This is supported by experimental studies showing that diverting people's away from acute leads experiencing less Theoretical work has suggested this phenomenon may present top-down modulatory mechanism for persistent as well. However, conclusive empirical evidence lacking. To fill gap, we used preregistered, double-blind, between-subject study design investigate whether performing tailored, demanding, and engaging working memory (difficult) vs requires mental effort performed (easy), could lead lower development secondary hypersensitivity-a hallmark central sensitization. Eighty-five healthy volunteers, randomly assigned one 2 conditions, visual with different load (difficult easy), while hypersensitivity was induced on their nondominant forearm using high-frequency stimulation. assess hypersensitivity, sensitivity mechanical stimuli measured 3 times: T0, baseline 20 (T1) 40 (T2) minutes after procedure. We did not observe any significant difference between groups, neither terms intensity nor its spatial extent. Our results suggest modulation through might sufficient affect sensitization hypersensitivity.

Язык: Английский

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The mutually reinforcing dynamics between pain and stress: mechanisms, impacts and management strategies

Frontiers in Pain Research, Год журнала: 2024, Номер 5

Опубликована: Ноя. 18, 2024

While distinct, pain and stress share complex biological psychological mechanisms that—despite their protective functions—can lead to clinically maladaptive changes requiring therapeutic intervention when they recur or persist. Recognized as “worldwide epidemics” of modern life, both conditions significantly affect an individual's quality functioning, well-being; without timely intervention, can become chronic, leading substantial economic costs via healthcare expenses, lost wages, reduced productivity. Evidence suggests that not only feed into but exacerbate each other through a “vicious cycle,” driven by overlapping physiological, cognitive, social mechanisms, indicating mutually reinforcing dynamics between stress. In this review, we highlight the importance recognizing promote persistence stress: (1) key physiological processes like neuroplasticity, neuroendocrine dysfunction, chronic inflammation; (2) cognitive behavioral patterns such fear avoidance, hypervigilance, catastrophizing; along with (3) social, lifestyle, environmental influences, socioeconomic status, lack support, lifestyle choices. Through case study, illustrate real-world implications vicious cycle perpetuating conditions. We call for paradigm shift in management, advocating holistic management strategy encompassing pharmacological, psychological, interventions address underlying biopsychosocial factors. By fostering greater awareness among primary care practitioners professionals, it is possible better support individuals breaking stress, thereby enhancing life overall well-being.

Язык: Английский

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Critical reflections on medication overuse headache in patients with migraine: An unsolved riddle in nociception

Neurobiology of Pain, Год журнала: 2025, Номер 17, С. 100179 - 100179

Опубликована: Янв. 1, 2025

Migraine chronification very frequently exposes patients to the inevitable risk of excessive symptomatic intake that, in turn, prompts development medication overuse headache (MOH). The latter further compromises severity establishing a vicious cycle and relapsing head pain that critically worsens overall clinical status patients. A great deal attention has been focused on MOH pathogenesis, thanks preclinical studies knowledge about this disorder is now remarkably advanced. Still, some open questions remain regarding issues related neurobiology neurochemistry underpinning patients, as well remedies capable interrupting pronociceptive cephalic sensitization drug overuse. Here, critical reappraisal these provided an attempt gain deeper insight promote debate still represents conundrum field nociception.

Язык: Английский

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IMPDH2's Central Role in Cellular Growth and Diseases: A Potential Therapeutic Target

Cell Proliferation, Год журнала: 2025, Номер unknown

Опубликована: Апрель 19, 2025

IMPDH2 is a rate-limiting enzyme in guanine nucleotide biosynthesis. It plays diverse roles various physiological and pathological processes: metabolism, inflammation, immune function, ribosomal stress. Structural or regulatory alterations are linked to significant health issues, critical relevance disease progression. We aim underscore the potential of as promising therapeutic target for clinical applications.

Язык: Английский

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From didactic explanations to co-design, sequential art and embodied learning: challenges, criticisms and future directions of patient pain education

Frontiers in Pain Research, Год журнала: 2025, Номер 6

Опубликована: Май 9, 2025

Pain Neuroscience Education (PNE) emerged over two decades ago in response to the incoherence between evidence-based pain management strategies, and consumer clinician understandings of “how works”. Many clinical trials have investigated effects PNE either as a standalone intervention or embedded within more complex care package, with mixed results. A range research methods been used explore inconsistent PNE. Together they (i) identify significant shortcomings limitations (ii) raise possibility that gaining broadly scientifically accurate understanding works” may be critical for subsequent disability improvements. Both learnings strongly suggest we need do better. Extensive incorporating several interest-holders has led updated content language criticisms both are addressed. The method also updated, integration educational frameworks, teaching strategies tactics, patient resources tools all aim promote likelihood patients will learn key concepts operationalise them improve their pain, function quality life. Science is differentiate new approach from

Язык: Английский

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Betulinic acid analogs inhibit N- and T-type voltage-gated calcium channels to attenuate nerve-injury associated neuropathic and formalin models of pain

Neurobiology of Pain, Год журнала: 2023, Номер 13, С. 100116 - 100116

Опубликована: Янв. 1, 2023

Over the past three decades, there has been a significant growth in use of natural products, with approximately 80% individuals using them for some aspect primary healthcare. Our laboratories have identified and studied compounds analgesic effects from dry land plants or their associated fungus during ten years. Here, we isolated characterized thirteen betulin analogs fifteen betulinic acid capacity to prevent calcium influx brought on by depolarization sensory neurons. The vitro inhibition voltage-gated channels top drugs was then assessed whole cell patch clamp electrophysiology. In vivo experiments, conducted at two sites, evaluated best compound acute tonic, neuropathic, inflammatory, post-operative visceral models pain. We found that analog 8 inhibited rat dorsal root ganglion neurons inhibiting N- (CaV2.2) T- (CaV3) type channels. Moreover, intrathecal delivery had activity both spared nerve injury model neuropathic pain tonic induced formalin. results presented herein highlight potential antinociceptive properties set stage development novel non-opioid therapeutics based triterpenoid scaffold acid.

Язык: Английский

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