Podcasts about nociceptor

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.30.547260v1?rss=1 Authors: Tian, J., Bavencoffe, A. G., Zhu, M. X., Walters, E. T. Abstract: Nociceptor cell bodies generate spontaneous discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia (DRGs) have shown that prior pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Here we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na+ and/or Ca2+, and that Ca2+-permeable channels are especially important for larger DSFs. Partial reduction of the amplitude and/or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na+ and/or Ca2+ produces DSFs that are poised to reach AP threshold if resting membrane potential (RMP) depolarizes, AP threshold decreases, and/or DSFs become enhanced -- all of which have been reported under painful neuropathic and inflammatory conditions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.01.526526v1?rss=1 Authors: Jain, A., Gyori, B., Hakim, S., Bunga, S., Taub, D. G., Ruiz-Cantero, M. C., Tong-Li, C., Andrews, N., Sorger, P. K., Woolf, C. J. Abstract: Inflammatory pain associated with tissue injury and infections, results from the heightened sensitivity of the peripheral terminals of nociceptor sensory neurons in response to exposure to inflammatory mediators. Targeting immune-derived inflammatory ligands, like prostaglandin E2, has been effective in alleviating inflammatory pain. However, the diversity of immune cells and the vast array of ligands they produce make it challenging to systematically map all neuroimmune pathways that contribute to inflammatory pain. Here, we constructed a comprehensive and updatable database of receptor-ligand pairs and complemented it with single-cell transcriptomics of immune cells and sensory neurons in three distinct inflammatory pain conditions, to generate injury-specific neuroimmune interactomes. We identified cell-type-specific neuroimmune axes that are common, as well as unique, to different injury types. This approach successfully predicts neuroimmune pathways with established roles in inflammatory pain as well as ones not previously described. We found that thrombospondin-1 produced by myeloid cells in all three conditions, is a negative regulator of nociceptor sensitization, revealing a non-canonical role of immune ligands as an endogenous reducer of peripheral sensitization. This computational platform lays the groundwork to identify novel mechanisms of immune-mediated peripheral sensitization and the specific disease contexts in which they act. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.18.520950v1?rss=1 Authors: Sliwinski, C., Heutehaus, L., Taberner, F. J., Weiss, L., Kampanis, V., Tolou-Dabbaghian, B., Cheng, X., Motsch, M., Heppenstall, P. A., Kuner, R., Franz, S., Lechner, S. G., Weidner, N., Puttagunta, R. Abstract: Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptors before SCI mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations from contusion SCI mice 7 days after injury makes a significant direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519572v1?rss=1 Authors: Ippolito, D., Glauser, D. A. Abstract: Nociceptive habituation is a conserved process through which pain-sensitivity threshold is adjusted based on past sensory experience and which may be dysregulated in human chronic pain conditions. Noxious heat habituation in C. elegans involves the nuclear translocation of CaM kinase-1 (CMK-1) in the FLP thermo-nociceptors neurons, causing reduced animal heat sensitivity and avoidance responses. The phosphorylation of CMK-1 on T179 by CaM kinase kinase-1 (CKK-1) is required for nuclear entry. Recently, we identified a specific Nuclear Export Sequence (NES) required to maintain CMK-1 in the cytoplasm at rest (20 {degrees}C) and showed that Ca2+/CaM binding is sufficient to enhance CMK-1 affinity for IMA-3 via a specific Nuclear Localization Signal (NLS) in order to promote nuclear entry after persistent heat stimulation (90 min at 28{degrees}C) (Ippolito et al., 2021). Here, we identified additional functional NES and NLS on CMK-1, whose activity can counteract previously identified elements. Furthermore, we clarify the relationship between the CaM-binding-dependent and T179-dependent effects. T179 phosphorylation can promotes nuclear entry both downstream of CaM-binding and as part of an independent/parallel pathway. Moreover, T179 phosphorylation can also produce the opposite effect by promoting nuclear export. Taken together, our studies show that multiple calcium-dependent regulatory mechanisms converge to bias the activity pattern across a network of NES/NLS elements, in order to activate CMK-1 nucleo-cytoplasmic shuttling, change its localization equilibrium and actuate stimulation-dependent nociceptive plasticity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

"Skupcie się" - apeluje do dzieci niejeden nauczyciel, a może koncentracja nie jest dla nich najważniejsza? Koncentrujemy się na bólu wiedząc, że jest sygnałem alarmowym, ale czy spełnia on też inne role? W dzisiejszym odcinku usłyszycie też o tym jak nawigują owady podczas migracji przez morze oraz jak zwierzęta reagują na turystów odwiedzających parki narodowe. Tradycyjnie proszę Was o subskrybowanie i lajkowanie, dajcie tez znać swoim znajomym o istnieniu podkastu Naukowo, to dla mnie bardzo cenne w docieraniu do nowych słuchaczy. Zapraszam serdecznie na sobotni odcinek!Jeśli uznasz, że warto wspierać ten projekt to zapraszam do serwisu Patronite, każda dobrowolna wpłata od słuchaczy pozwoli mi na rozwój i doskonalenie tego podkastu, bardzo dziękuję za każde wsparcie!Zapraszam również na Facebooka, Twittera i Instagrama, każdy lajk i udostępnienie pomoże w szerszym dotarciu do słuchaczy, a to jest teraz moim głównym celem :) Na stronie Naukowo.net znajdziesz więcej interesujących artykułów naukowych, zachęcam również do dyskusji na tematy naukowe, dzieleniu się wiedzą i nowościami z naukowego świata na naszym serwerze Discord - https://discord.gg/mqsjM5THXrŹródła użyte przy tworzeniu odcinka:Nathaniel J.Blanco, Brandon M.Turner, Vladimir M.Sloutsky. "The benefits of immature cognitive control: How distributed attention guards against learning traps", https://doi.org/10.1016/j.jecp.2022.105548Mira L. T. Sytsma, Tania Lewis, Beth Gardner, Laura R. Prugh, "Low levels of outdoor recreation alter wildlife behaviour", https://doi.org/10.1002/pan3.10402Hawkes Will L., Weston Scarlett T., Cook Holly, Doyle Toby, Massy Richard, Guri Eva Jimenez, Wotton Jimenez Rex E. and Wotton Karl R. 2022Migratory hoverflies orientate north during spring migrationBiol. Lett.182022031820220318, http://doi.org/10.1098/rsbl.2022.0318Daping Yang, Amanda Jacobson, Kimberly A. Meerschaert, Joseph Joy Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel A. Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon S. Wu, Liwen Deng, Michael D. Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis L. Kasper, Bana Jabri, Jun R. Huh, Malin Johansson, Jay R. Thiagarajah, Samantha J. , iesenfeld, Isaac M. Chiu. "Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection", https://doi.org/10.1016/j.cell.2022.09.024

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.04.510784v1?rss=1 Authors: Xie, Y.-F., Yang, J., Ratte, S., Prescott, S. A. Abstract: Nociceptive sensory neurons convey pain signals to the CNS. Nociceptor hyperexcitability amplifies those signals, causing pain hypersensitivity. Reducing nociceptor excitability should mitigate that hypersensitivity, consistent with the effects of loss-of-function mutations in voltage-gated sodium (NaV) channels like NaV1.7. Yet efforts to phenocopy such mutations pharmacologically have failed in clinical trials. This failure may stem from the degenerate nature of nociceptor excitability. Here, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. If NaV1.3 and/or NaV1.8 levels are high enough to maintain nociceptor excitability, selectively blocking NaV1.7 (e.g. with PF-05089771) becomes inconsequential. We demonstrate shifts in drug efficacy by comparing neurons tested after different numbers of days in vitro (DIV): Nociceptor excitability relies on NaV1.8 at DIV0 but that responsibility shifts to NaV1.7 and NaV1.3 on DIV4-7. A similar shift in NaV-dependence occurs in vivo, following inflammation, and impacts the ability of PF-05089771 to modulate pain sensitivity. These results demonstrate that nociceptors are surprisingly flexible in using different NaV isoforms to regulate excitability. This flexibility poses a serious problem for subtype-selective drugs whose efficacy hinges on such vagaries. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.15.508178v1?rss=1 Authors: Mitchell, M., Cook, L. F., Shiers, S., Tavares-Ferreira, D., Akopian, A. N., Dussor, G., Price, T. J. Abstract: Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the CNS. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS pre-mutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated DRG neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation-dependent nociceptive sensitization. Activity-dependent, local translation is a key mechanism for enhancing primary nociceptor excitability which promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human dorsal root ganglion (DRG) and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane-associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene-related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Detailed lecture about the very important and complicated thyroid hormone system and how to treat problems; Balancing antibiotics, probiotics and prebiotics; Low dose naltrexone helps treat long term COVID-19 symptoms; All about uterine fibroids -- supplements to counter insulin resistance helps; A new type of sensory cell has been discovered in your skin; Glial cells in the brain continue to grow after death; Sorry to be so late this week!

Detailed lecture about the very important and complicated thyroid hormone system and how to treat problems; Balancing antibiotics, probiotics and prebiotics; Low dose naltrexone helps treat long term COVID-19 symptoms; All about uterine fibroids -- supplements to counter insulin resistance helps; A new type of sensory cell has been discovered in your skin; Glial cells in the brain continue to grow after death; Sorry to be so late this week!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.04.368597v1?rss=1 Authors: Klein, A., Solinski, H. J., Malewicz, N., Ieong, H. F.-h., Shimada, S., Hartke, T. V., Wooten, M., Wu, G., Hoon, M. A., LaMotte, R. H., Ringkamp, M. Abstract: In human, intradermal administration of {beta}-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1 respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (Macaca nemestrina), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22 and histamine, that activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.31.231753v1?rss=1 Authors: Tavares-Ferreira, D., Ray, P., Sankaranarayanan, I., Mejia, G. L., Wangzhou, A., Shiers, S., Uttarkar, R. S., Megat, S., Barragan-Iglesias, P., Dussor, G., Akopian, A. N., Price, T. J. Abstract: Background: There are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences. Methods: We used Translating Ribosome Affinity Purification (TRAP) sequencing and behavioral pharmacology to test the hypothesis that nociceptor (Nav1.8 expressing neurons) translatomes would differ by sex. Results: We found 66 genes whose mRNA were sex-differentially bound to nociceptor ribosomes. Many of these genes have known neuronal functions but have not been explored in sex differences in pain. We focused on Ptgds, which was increased in female mice. The mRNA encodes the prostaglandin D2 (PGD2) synthesizing enzyme. We observed increased Ptgds protein and PGD2 in female mouse DRG. The Ptgds inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in females. Conversely, female mice responded more robustly to another major prostaglandin, PGE2, than did male mice. Ptgds protein expression was also higher in female cortical neurons, suggesting DRG findings may be generalizable to other nervous system structures. Conclusions: Nociceptor TRAP sequencing (TRAP-seq) reveals unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins. Our results demonstrate that translatome analysis reveals physiologically relevant sex differences important for fundamental protective behaviors driven by nociceptors. Copy rights belong to original authors. Visit the link for more info

¡Gracias por escuchar! En este episodio hablaré del papel que juega la inflamación en la generación de dolor en pacientes con osteoartritis. La OA tiene una morbilidad asociada sustancial y constituye un creciente problema de salud pública derivado en gran medida del envejecimiento poblacional. Los síntomas de la OA pueden ser funcionales pero se manifiestan principalmente como dolor y el manejo de la enfermedad se centra principalmente en su control.Agradezco que escuchen este podcast y les recuerdo que se encuentra disponible en el catálogo de iTunes, en Google Play (siendo accesible a través del gestor de podcasts de su dispositivo móvil), así como en Spotify. Agradezco también su retroalimentación en estas plataformas y les pido amablemente que califiquen el podcast ya que esto es importante para su continuado desarrollo.A continuación se enlistan las referencias mencionadas en este episodio: Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. 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David Bennett discusses painful and painless channelopathies.

Doctors and patients at the Royal Free Hospital's Pain Clinic and at the Real Health Institute explain how chronic pain works

Transcript -- Doctors and patients at the Royal Free Hospital's Pain Clinic and at the Real Health Institute explain how chronic pain works

Doctors and patients at the Royal Free Hospital's Pain Clinic and at the Real Health Institute explain how chronic pain works

Transcript -- Doctors and patients at the Royal Free Hospital's Pain Clinic and at the Real Health Institute explain how chronic pain works