Mapping the neuroethological signatures of pain, analgesia, and recovery in mice

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2811 - 2830.e8

Published: July 12, 2023

Language: Английский

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

Frontiers in Pain Research, Journal Year: 2023, Volume and Issue: 4

Published: Sept. 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.

Language: Английский

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B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(766)

Published: Sept. 25, 2024

Neuroimmune interactions are essential for the development of neuropathic pain, yet contributions distinct immune cell populations have not been fully unraveled. Here, we demonstrate critical role B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury male and female mice. Depletion with a single injection anti-CD20 monoclonal antibody at time prevented allodynia. cell–deficient (muMT) mice were similarly spared from Nerve was associated increased immunoglobulin G (IgG) accumulation ipsilateral lumbar dorsal root ganglia (DRGs) spinal cords. IgG colocalized sensory neurons macrophages DRGs microglia also accumulated DRG samples human donors chronic colocalizing marker satellite glia. RNA sequencing revealed population naive mouse DRGs. A transcriptional signature enriched pain. Passive transfer injured induced allodynia muMT recipient The pronociceptive effects likely mediated through complexes interacting Fc gamma receptors (FcγRs) expressed by neurons, microglia, macrophages, given that both hyperexcitability dissociated abolished nerve-injured FcγR-deficient Consistently, passive lost These data reveal cell–IgG–FcγR axis is required pain

Language: Английский

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Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 9, 2025

Abstract Background Neuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation cannabinoid type-1 receptors (CB1Rs) transient receptor potential vanilloid 1 (TRPV1). However, the role AEA these in nociceptors after SCI remains unclear. Results In this study, we investigated effects its on hyperexcitability mouse dorsal root ganglion (DRG) neurons SCI. Using a whole-cell patch-clamp technique, found that timing SCI-induced paralleled an increase endocannabinoid content. The expression TRPV1 CB1R was also upregulated at different time points High-dose extracellular administration increased naive DRG neurons, leading transition rapidly accommodating (RA) hypoexcitable state highly excitable non-accommodating (NA) state. These AEA-induced transitions were facilitated by transcription. Pharmacological Ca 2+ imaging experiments revealed induced via AEA-TRPV1-Ca pathway, whereas CB1Rs reduced maintained cytosolic concentration ([Ca ] cyto ) low levels early stages As SCI, adaptive neuroprotection transitioned maladaptive hyperactive state, sustained pain. Conclusions Taken together, study provides new insights into how endocannabinoids regulate nociceptor activity offering targets for treatment neuropathic

Language: Английский

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Differential modification of ascending spinal outputs in acute and chronic pain states

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Pain hypersensitivity arises from the induction of plasticity in peripheral and spinal somatosensory neurons, which modifies nociceptive input to brain, altering pain perception. We applied longitudinal calcium imaging dorsal projection neurons determine whether how representation stimuli anterolateral tract, principal pathway transmitting signals changes between distinct states. In healthy mice, we identified stable outputs selective for cooling or warming a neuronal ensemble activated by noxious thermal mechanical stimuli. Induction acute sensitization topical capsaicin transiently re-tuned output encode low-intensity contrast, nerve injury resulted persistent suppression innocuous coupled with activation normally silent population high-threshold neurons. These results demonstrate differential modulation brain during neuropathic

Language: Английский

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Humanized NaV1.8 rats overcome cross-species potency shifts in developing novel NaV1.8 inhibitors

Neurobiology of Pain, Journal Year: 2025, Volume and Issue: unknown, P. 100182 - 100182

Published: March 1, 2025

Voltage-gated sodium channel isoform 1.8 (NaV1.8) has emerged as a promising pharmaceutical target for the treatment of acute and chronic pain. However, highly selective potent inhibitors this have been difficult to develop only recently advanced clinical testing. Our efforts NaV1.8 small molecule yielded series molecules with favorable in vitro potency selectivity against human but exhibited dramatic rightward shifts rodent channel, severely limiting vivo screening candidate selection. In anticipation supporting drug discovery efforts, transgenic rat line expressing lieu was developed. Utilizing these humanized animals, our chemical matter freshly isolated DRG neurons consistent values, enabling work progress. We demonstrate capsaicin-induced nocifensive behaviors (CNB) moderate throughput assay, from which we pharmacokinetic-pharmacodynamic (PK-PD) vitro-in correlation (IVIVC) relationships. identified MSD199 inhibitor pain efficacy assessed it traditional inflammatory (Complete Freund's Adjuvant) neuropathic (spinal nerve ligation) behavioral assays where shown significantly reduce pain-related behaviors. Overall, utility animals when cross-species are observed within an otherwise series.

Language: Английский

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The dual role of microglia in neuropathic pain after spinal cord injury: Detrimental and protective effects

Experimental Neurology, Journal Year: 2023, Volume and Issue: 370, P. 114570 - 114570

Published: Oct. 16, 2023

Language: Английский

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

Brain, Journal Year: 2024, Volume and Issue: 147(9), P. 2991 - 2997

Published: July 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.

Language: Английский

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Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance

Pain, Journal Year: 2023, Volume and Issue: 165(4), P. 893 - 907

Published: Oct. 20, 2023

Abstract Nociceptor cell bodies generate “spontaneous” discharge that can promote ongoing pain in persistent conditions. Little is known about the underlying mechanisms. Recordings from nociceptor (somata) dissociated rodent and human dorsal root ganglia have shown previous vivo associated with low-frequency controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced transient inward currents across somal input resistance. Using mouse nociceptors, we show DSFs are high resistance over a wide range potentials, including depolarized levels where approach action (AP) threshold. Input both amplitude frequency were increased neurons exhibiting activity. Ion substitution experiments indicated phase generated opening channels permeable to Na + or Ca 2+ -permeable especially important for larger DSFs. Partial reduction perfusion pharmacological inhibitors small but significant contributions Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, N-type channels. Less specific blockers suggested contribution NALCN channels, global knockout role Nav1.9. The combination plus background activity diverse ion produces poised reach AP threshold if resting depolarizes, decreases, become enhanced—all which occur under painful neuropathic inflammatory

Language: Английский

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MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 14, 2023

Abstract Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain preclinical models and patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined that drive spontaneous (SA), none these tested directly on spontaneously active human nociceptors. Using cultured DRG recovered during thoracic vertebrectomy surgeries, we show inhibition mitogen activated protein kinase interacting (MNK) with eFT508 (25 nM) reverses SA sensory associated painful dermatomes. MNK nociceptors decreased action potential amplitude produced alterations the magnitude afterhyperpolarizing currents suggesting modification Na + K channel downstream inhibition. The effects took minutes to emerge were reversible over time washout. led profound loss eIF4E Serine 209 phosphorylation, specific target kinase, within 2 min drug treatment, consistent rapid electrophysiology experiments. Our results create compelling case for future testing inhibitors clinical trials pain. Conflict interest TJP co-founder 4E Therapeutics, company developing other authors declare no conflicts interest.

Language: Английский

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