| 1. |
- Kalliomäki, Maija, et al.
(författare)
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Structural and functional differences between neuropathy with and without pain?
- 2011
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 231:2, s. 199-206
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury-related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4 degrees C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Petersson, Marcus E., et al.
(författare)
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Differential Axonal Conduction Patterns of Mechano-Sensitive and Mechano-Insensitive Nociceptors - A Combined Experimental and Modelling Study
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e103556-
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (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 sensitization 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 Na(V)1.7 and Na(V)1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less K-dr and Na(V)1.8 in combination with more Na(V)1.7 and Na+/ K(+)AT-Pase. 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.
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| 5. |
- Schmidt, Roland, et al.
(författare)
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Double spikes to single electrical stimulation correlates to spontaneous activity of nociceptors in painful neuropathy patients.
- 2012
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 153:2, s. 391-8
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Tidskriftsartikel (refereegranskat)abstract
- Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity. In 11 of 105 nociceptors, double spiking was found, with 1fibre even showing triple spikes on electrical stimulation. The interval between the main action potential and the multiple spikes ranged from 13 to 100ms. There was a significant association between spontaneous activity and multiple spiking in C nociceptors, with spontaneous activity being present in 9 of 11 fibres with multiple spiking, but only in 21 of 94 nociceptors without multiple spiking (P<.005, Fisher exact test). Among the 75 C nociceptors without spontaneous activity, only 2 nociceptors showed multiple spiking. In 8 neuropathy patients without pain, double spiking was found only in 4 of 90 nociceptors. Multiple spiking of nociceptors coincides with spontaneous activity in nociceptors of painful neuropathy patients. We therefore conclude that rather than being a generic sign of neuropathy, multiple spiking is linked to axonal hyperexcitability and spontaneous activity of nociceptors. It is still unclear whether it also is mechanistically related to the clinical pain level.
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| 6. |
- Schmidt, Roland, et al.
(författare)
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Time course of acetylcholine-induced activation of sympathetic efferents matches axon reflex sweating in humans
- 2011
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Ingår i: Journal of the peripheral nervous system. - : Wiley. - 1085-9489 .- 1529-8027. ; 16:1, s. 30-36
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Tidskriftsartikel (refereegranskat)abstract
- Action potentials from postganglionic C-fibres were recorded in healthy volunteers by microneurography in the peroneal nerve. Their responsiveness to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation. Twenty units were classified as sympathetic efferent units. Acetylcholine (ACh) iontophoresis (10%, 1 mA, 1 min) inside their innervation territory activated 8 of 20 sympathetic fibres with a mean delay of 61 +/- 12 s, peak response at 175 +/- 38 s, and a duration of 240 +/- 42 s, whereas iontophoresis of saline did not activate any of them. The time course of neuronal activation correlated with the axon reflex sweating measured by an evaporimeter in a separate session (delay 76 +/- 9 s, peak at 195 +/- 12 s, decline to 50% of peak 312 +/- 25 s). No ACh-induced vasoconstriction was observed by laser Doppler scanning (n = 11) even after depletion of neuropeptides by chronic topical capsaicin treatment (n = 8). We conclude that ACh iontophoresis activates about half of the sympathetic fibres in human skin and provokes a corresponding axon reflex sweating. The absence of ACh-induced vasoconstriction even after the depletion of neuropeptides by capsaicin suggests that only sudomotor fibres, but not sympathetic vasoconstrictor fibres are activated by this stimulus.
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| 7. |
- Tigerholm, Jenny, et al.
(författare)
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Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors
- 2014
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 111:9, s. 1721-1735
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
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