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37 results on '"Obreja, Otilia"'

16. TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors

Author

Jonas, Robin, Prato, Vincenzo, Lechner, Stefan G., Groen, Gerbrand, Obreja, Otilia, Werland, Fiona, Rukwied, Roman, Klusch, Andreas, Petersen, Marlen, Carr, Richard W., Schmelz, Martin, and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)

Subjects
axonal calcium imaging, nervous system, Cellular Neuroscience, action potential conduction, activity-dependent slowing of conduction, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, tetrodotoxin, nociceptor classes, lcsh:RC321-571
Abstract

Pronounced activity-dependent slowing of conduction has been used to characterize mechano-insensitive, “silent” nociceptors and might be due to high expression of NaV1.8 and could, therefore, be characterized by their tetrodotoxin-resistance (TTX-r). Nociceptor-class specific differences in action potential characteristics were studied by: (i) in vitro calcium imaging in single porcine nerve growth factor (NGF)-responsive neurites; (ii) in vivo extracellular recordings in functionally identified porcine silent nociceptors; and (iii) in vitro patch-clamp recordings from murine silent nociceptors, genetically defined by nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) expression. Porcine TTX-r neurites (n = 26) in vitro had more than twice as high calcium transients per action potential as compared to TTX-s neurites (n = 18). In pig skin, silent nociceptors (n = 14) characterized by pronounced activity-dependent slowing of conduction were found to be TTX-r, whereas polymodal nociceptors were TTX-s (n = 12) and had only moderate slowing. Mechano-insensitive cold nociceptors were also TTX-r but showed less activity-dependent slowing than polymodal nociceptors. Action potentials in murine silent nociceptors differed from putative polymodal nociceptors by longer duration and higher peak amplitudes. Longer duration AP in silent murine nociceptors linked to increased sodium load would be compatible with a pronounced activity-dependent slowing in pig silent nociceptors and longer AP durations could be in line with increased calcium transients per action potential observed in vitro in TTX-resistant NGF responsive porcine neurites. Even though there is no direct link between slowing and TTX-resistant channels, the results indicate that axons of silent nociceptors not only differ in their receptive but also in their axonal properties.

Published
2020

22. Differential Axonal Conduction Patterns of Mechano- Sensitive and Mechano-Insensitive Nociceptors – A Combined Experimental and Modelling Study

Author

Petersson, Marcus E., Obreja, Otilia, Lampert, Angelika, Carr, Richard W., Schmelz, Martin, and Fransén, Erik

Subjects
Medizinische Fakultät, ddc:610
Abstract

Cutaneous pain sensations are mediated largely by -nociceptors consisting of both mechano-sensitive (CM) and mechanoinsensitive(CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after ensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+- ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.

Published
2014

23. C-Fiber Recovery Cycle Supernormality Depends on Ion Concentration and Ion Channel Permeability

Author

Tigerholm, Jenny, Petersson, Marcus E., Obreja, Otilia, Eberhardt, Esther, Namer, Barbara, Weidner, Christian, Lampert, Angelika, Carr, Richard, Schmelz, Martin, Fransén, Erik, Tigerholm, Jenny, Petersson, Marcus E., Obreja, Otilia, Eberhardt, Esther, Namer, Barbara, Weidner, Christian, Lampert, Angelika, Carr, Richard, Schmelz, Martin, and Fransén, Erik

Abstract

Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed. The model represents the spatial extent of the axon including its passive properties as well as ion channels and the Na/K-ATPase ion pump. Ionic concentrations were represented inside and outside the membrane. The model was able to replicate the typical transitions in excitability from subnormal to supernormal observed empirically following a conducted action potential. In the model, supernormality depended on the degree of conduction slowing which in turn depends upon the frequency of stimulation, in accordance with experimental findings. In particular, we show that activity-dependent conduction slowing is produced by the accumulation of intraaxonal sodium. We further show that the supernormal phase results from a reduced potassium current K-dr as a result of accumulation of periaxonal potassium in concert with a reduced influx of sodium through Na(v)1.7 relative to Na(v)1.8 current. This theoretical prediction was supported by data from an in vitro preparation of small rat dorsal root ganglion somata showing a reduction in the magnitude of tetrodotoxin-sensitive relative to tetrodotoxin - resistant whole cell current. Furthermore, our studies provide support for the role of depolarization in supernormality, as previously suggested, but we suggest that the basic mechanism depends on changes in ionic concentrations inside and outside the axon. The understanding of the mechanisms underlying repetitive discharges in recovery cycles may provide insight into mechan, QC 20150504

Published
2015
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25. Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors

Author

Tigerholm, Jenny, Petersson, Marcus, Obreja, Otilia, Lampert, Angelika, Carr, Richard, Schmelz, Martin, Fransén, Erik, Tigerholm, Jenny, Petersson, Marcus, Obreja, Otilia, Lampert, Angelika, Carr, Richard, Schmelz, Martin, and Fransén, Erik

Abstract

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients., QC 20140602. Updated from manuscript to article in journal.

Published
2014
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28. Modelling post spike excitability changes in peripheral C-fibres

Author

Tigerholm, Jenny, Petersson, Marcus, Obreja, Otilia, Lampert, Angelika, Carr, Richard, Schmelz, Martin, Fransén, Erik, Tigerholm, Jenny, Petersson, Marcus, Obreja, Otilia, Lampert, Angelika, Carr, Richard, Schmelz, Martin, and Fransén, Erik

Abstract

QS 2012

Published
2012

37. IL-1 beta potentiates heat-activated currents in rat sensory neurons: involvement of IL-1RI, tyrosine kinase, and protein kinase C.

Author

Obreja O, Rathee PK, Lips KS, Distler C, and Kress M

Subjects
Animals, Calcium metabolism, Cells, Cultured, Enzyme Inhibitors pharmacology, Female, Ganglia, Spinal cytology, Ganglia, Spinal drug effects, Ganglia, Spinal metabolism, Gene Expression, Genistein pharmacology, Hot Temperature, In Situ Hybridization, Indoles pharmacology, Maleimides pharmacology, Membrane Potentials drug effects, Neurons, Afferent physiology, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptors, Interleukin-1 genetics, Receptors, Interleukin-1 physiology, Receptors, Interleukin-1 Type I, Receptors, Interleukin-1 Type II, Staurosporine pharmacology, Suramin pharmacology, Time Factors, Interleukin-1 pharmacology, Neurons, Afferent drug effects
Abstract

Interleukin 1 beta (IL-1 beta) is a proinflammatory cytokine that maintains thermal hyperalgesia and facilitates the release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Brief applications of IL-1 beta to nociceptive neurons yielded a potentiation of heat-activated inward currents (Iheat) and a shift of activation threshold toward lower temperature without altering intracellular calcium levels. The IL-1 beta-induced heat sensitization was not dependent on G-protein-coupled receptors but was mediated by activation of protein kinases. The nonspecific protein kinase inhibitor staurosporine, the specific protein kinase C inhibitor bisindolylmaleimide BIM1, and the protein tyrosine kinase inhibitor genistein reduced the sensitizing effect of IL-1 beta whereas negative controls were ineffective. RT-PCR and in situ hybridization revealed IL-1RI but not RII expression in neurons rather than surrounding satellite cells in rat dorsal root ganglia. IL-1 beta acts on sensory neurons to increase their susceptibility for noxious heat via an IL-1RI/PTK/PKC-dependent mechanism.

Published
2002
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