| 1. |
- Babes, Alexandru, et al.
(författare)
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Photosensitization in porphyrias and photodynamic therapy involves TRPA1 and TRPV1
- 2016
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Ingår i: The Journal of Neuroscience. - 0270-6474. ; 36:19, s. 5264-5278
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Tidskriftsartikel (refereegranskat)abstract
- Photosensitization, an exaggerated sensitivity to harmless light, occurs genetically in rare diseases, such as porphyrias, and in photodynamic therapy where short-term toxicity is intended. A common feature is the experience of pain from bright light. In human subjects, skin exposure to 405 nm light induced moderate pain, which was intensified by pretreatment with aminolevulinic acid. In heterologous expression systems and cultured sensory neurons, exposure to blue light activated TRPA1 and, to a lesser extent, TRPV1 channels in the absence of additional photosensitization. Pretreatment with aminolevulinic acid or with protoporphyrin IX dramatically increased the light sensitivity of both TRPA1 and TRPV1 via generation of reactive oxygen species. Artificial lipid bilayers equipped with purified human TRPA1 showed substantial single-channel activity only in the presence of protoporphyrin IX and blue light. Photosensitivity and photosensitization could be demonstrated in freshly isolated mouse tissues and led to TRP channel-dependent release of proinflammatory neuropeptides upon illumination. With antagonists in clinical development, these findings may help to alleviate pain during photodynamic therapy and also allow for disease modification in porphyria patients.
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| 2. |
- Eberhardt, Mirjam, et al.
(författare)
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H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway.
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5:Jul 15
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Tidskriftsartikel (refereegranskat)abstract
- Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H2S. We show that H2S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H2S-evoked vasodilatatory effects largely depend on NO production and activation of HNO-TRPA1-CGRP pathway. We propose that this neuroendocrine HNO-TRPA1-CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system.
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| 3. |
- Jonas, Robin, et al.
(författare)
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Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain
- 2018
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Ingår i: Annals of Neurology. - : WILEY. - 0364-5134 .- 1531-8249. ; 83:5, s. 945-957
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveDevelop and validate a low‐intensity sinusoidal electrical stimulation paradigm to preferentially activate C‐fibers in human skin.MethodsSinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of “silent” C‐nociceptors. Synchronized C‐fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small‐diameter neurons during transcutaneous 4‐Hz stimulation of the hindpaw (0.4mA).ResultsTranscutaneous sinusoidal current (0.05–0.4mA, 4Hz) activated “polymodal” C‐fibers (50% at ∼0.03mA) and “silent” nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1‐ms rectangular pulses (“polymodal” ∼3mA, “silent” ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon‐reflex erythema, both indicative of C‐nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) –3 and nonpainful skin sites of neuropathic pain patients by NRS –0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2.InterpretationSinusoidal electrical stimulation at 4Hz enables preferential activation of C‐nociceptors in pig and human skin that accommodates during ongoing (1‐minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment.
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| 4. |
- Kankel, Jennifer, et al.
(författare)
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Differential effects of low dose lidocaine on C-fiber classes in humans
- 2012
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Ingår i: Journal of Pain. - : Elsevier BV. - 1526-5900 .- 1528-8447. ; 13:12, s. 1232-1241
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Tidskriftsartikel (refereegranskat)abstract
- The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. Voltage-gated sodium channels are crucial for action potential generation and conduction, and their availability controls the amount of activity-dependent conduction velocity slowing. This important axonal property, as assessed by microneurography, is used to differentiate human mechanoinsensitive (silent) nociceptors from the classical polymodal nociceptors. In the current study, microneurography was used to assess axonal properties of the 2 main nociceptor classes in humans, before and after intradermal injection of lidocaine .1% or control saline solution in the receptive field. In mechanosensitive nociceptors, lidocaine reduced baseline conduction velocity and turned activity-dependent slowing into speeding of conduction. In contrast, mechanoinsensitive fibers were not affected in their baseline conduction velocity or their activity-dependent slowing, but probability of conduction block with repetitive stimulation increased. Recovery cycles showed reduced hyperpolarization in all C-fiber classes after lidocaine injections. These results support our hypothesis that sodium channel subtypes are differentially expressed in the 2 nociceptor classes of mechanosensitive C-fibers (CMs) and mechanoinsensitive C-fibers (CMis).Perspective: This study reveals that microneurography can be used to assess pharmacologicaleffects on single C-fibers directly in humans.
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| 5. |
- Kist, Andreas M., et al.
(författare)
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SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by micro-neurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p. M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p. M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.
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| 6. |
- Kleggetveit, Inge Petter, et al.
(författare)
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High spontaneous activity of C-nociceptors in painful polyneuropathy
- 2012
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 153:10, s. 2040-2047
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Tidskriftsartikel (refereegranskat)abstract
- Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C-nociceptors in painful and painless polyneuropathy patients to identify pain-specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C-fibres including 214 C-nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C-nociceptors. The mean percentage of C-nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P = .02). The difference was mainly due to more spontaneously active mechanoinsensitive C-nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P = .02). The percentage of sensitized mechanoinsensitive C-nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C-nociceptors (Kendall's tau = .55, P = .004). Moreover, spontaneous activity of mechanoinsensitive C-nociceptors correlated to less pronounced activity-dependent slowing of conduction (Kendall's tau = -.48, P = .009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C-nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C-nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.
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| 7. |
- Kleggetveit, Inge P., et al.
(författare)
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Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants
- 2016
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279 .- 2162-3279. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. Methods: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. Results: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. Conclusions: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.
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| 8. |
- Namer, Barbara, et al.
(författare)
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Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype
- 2017
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Ingår i: Frontiers in Neurology. - : FRONTIERS MEDIA SA. - 1664-2295. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of a-galactosidase A (Gla(-/0)). The skin innervation of Gla(-/0) mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla(-/0) mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla(-/0) nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla(-/0) nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.
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| 9. |
- Namer, Barbara, et al.
(författare)
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Endothelin1 activates and sensitizes human C-nociceptors
- 2007
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Ingår i: Pain. - Amsterdam : Elsevier. - 0304-3959 .- 1872-6623. ; 137:1, s. 41-49
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Tidskriftsartikel (refereegranskat)abstract
- Microneurography was used to record action potentials from afferent C-fibers in cutaneous fascicles of the peroneal nerve in healthy volunteers. Afferent fibers were classified according to their mechanical responsiveness to von Frey stimulation (75 g) into mechano-responsive and mechano-insensitive nociceptors. Various concentrations of Endothelin1 (ET1) and Histamine were injected into the receptive fields of C-fibers. Activation and heat sensitization were monitored. Axon reflex flare and psychophysical ratings were assessed after injection of ET1 and codeine into the forearms after pre-treatment with an H1 blocker or sodium chloride. 65% of mechanosensitive nociceptors were activated by ET1. One-third showed long lasting responses (>15 min). In contrast, none of thirteen mechano-insensitive fibers were activated. Sensitization to heat was observed in 62% of mechanosensitive and in 46% of mechano-insensitive fibers. Injection of ET1 produced a widespread axon reflex flare, which was suppressed by pre-treatment with an H1 receptor blocker. In addition, pain sensations were induced more often than itching by ET1 in contrast to codeine. No wheal was observed after injection of ET1. Both itching and pain were decreased after H1 blocker treatment. In summary: (1) In humans ET1 activates mechanosensitive, but not mechano-insensitive, nociceptors. (2) Histamine released from mast cells is not responsible for all effects of ET1 on C-nociceptors. (3) ET1 could have a differential role in pain compared to other chemical algogens which activate additionally or even predominantly mechano-insensitive fibers.
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| 10. |
- Namer, Barbara, et al.
(författare)
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Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Na(v)1.7
- 2015
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 156:9, s. 1637-1646
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Tidskriftsartikel (refereegranskat)abstract
- Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Na(v)1.7 (I848T, I228M), whereas no mutations of coding regions of Na(v)s were found in 5 patients with EM. Irrespective of Na(v)1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Na(v)1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Na(v)1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Na(v)1.7 could be explained by axonal depolarization and concomitant inactivation of Na(v)1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Na(v)1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
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