Enhancement of Ectopic Discharge in Regenerating A- and C-Fibers by Inflammatory Mediators
ABSTRACT Afferent A- and C-fibers regenerating into a nerve following peripheral nerve injury are exposed to inflammatory mediators released by Schwann cells, resident and invading macrophages, and other inflammatory cells. Here we tested the hypothesis that ongoing and evoked activity in these afferent fibers are enhanced by a mixture of inflammatory mediators [inflammatory soup (IS)] applied to the injured nerve. Using in vivo electrophysiology, regenerating afferent nerve fibers were studied 7-14 days after sural nerve crush lesion. The ectopic activity was studied before and <or=1.5 h after topical application of IS to the nerve in 73 C-fibers and 22 A-fibers that were either ectopically active before application of IS (61 C-fibers, 17 A-fibers) or recruited by IS (12 C-fibers, 5 A-fibers). More than one half of the C-fibers were activated by IS for <or=90 min after its removal. The majority of mechano- (23/38) and heat-sensitive (29/35) C-fibers as well as mechano-sensitive A-fibers (12/17) decreased their activation thresholds and/or increased the response magnitude to mechanical and/or heat stimulation of the nerve. Noxious cold sensitivity, but not nonnoxious cold sensitivity, was weakly influenced by IS. Some initially nonresponsive C- and A-fibers developed new ectopic properties, i.e., were recruited, and exhibited ongoing activity and/or could be activated by physiological stimuli after application of IS. The results suggest that inflammatory mediators may be critical to enhance ectopic excitability of regenerating afferent nerve fibers. These peripheral mechanisms may be important triggering and maintaining neuropathic pain.
Full-textDOI: · Available from: Wilfrid Jänig, Jul 03, 2014
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ABSTRACT: Tetrodotoxin-sensitive (TTX-s) spontaneous activity is recorded from the dorsal roots after peripheral nerve injury. Primary sensory neurons in the dorsal root ganglion (DRG) express multiple TTX-s voltage-gated sodium channel α-subunits (Navs). Since Nav1.3 increases, whereas all other Navs decrease, in the DRG neurons after peripheral nerve lesion, Nav1.3 is proposed to be critical for the generation of these spontaneous discharges and the contributions of other Navs have been ignored. Here, we re-evaluate the changes in expression of three other TTX-s Navs, Nav1.1, Nav1.6 and Nav1.7, in the injured 5th lumbar (L5) primary afferent components following L5 spinal nerve ligation (SNL) using in situ hybridization histochemistry and immunohistochemistry. While the overall signal intensities for these Nav mRNAs decreased, many injured DRG neurons still expressed these transcripts at clearly detectable levels. All these Nav proteins accumulated at the proximal stump of the ligated L5 spinal nerve. The immunostaining patterns of Nav1.6 and Nav1.7 associated with the nodes of Ranvier were maintained in the ipsilateral L5 dorsal root. Interestingly, putative proprioceptive neurons characterized by α3 Na(+)/K(+) ATPase-immunostaining specifically lacked Nav1.7 mRNA in naïve DRG but displayed de novo expression of this transcript following SNL. Nav1.7-immunoreactive fibers were significantly increased in the ipsilateral gracile nucleus where central axonal branches of the injured A-fiber afferents terminated. These data indicate that multiple TTX-s channel subunits could contribute to the generation and propagation of the spontaneous discharges in the injured primary afferents. Specifically, Nav1.7 may cause some functional changes in sensory processing in the gracile nucleus after peripheral nerve injury. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.Neuroscience 10/2014; 284C:693-706. DOI:10.1016/j.neuroscience.2014.10.027 · 3.33 Impact Factor
- Fertility and Sterility - FERT STERIL; 09/2011
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ABSTRACT: Intact and injured cutaneous C-fibers in the rat sural nerve are cold-, heat- and/or mechanosensitive. Cold-sensitive fibers are either low threshold type 1 cold-sensitive or high threshold type 2 cold-sensitive. The hypothesis was tested, in intact and injured afferent nerve fibers, that low-threshold cold-sensitive afferent nerve fibers are activated by the transient receptor potential melastatin 8 (TRPM8) agonist menthol, whereas high-threshold cold-sensitive C-fibers and cold-insensitive afferent nerve fibers are menthol-insensitive. In anesthetized rats activity was recorded from afferent nerve fibers in strands isolated from the sural nerve which was either intact or crushed 6 to 12 days before the experiment distal to the recording site. In all, 77 functionally identified afferent C-fibers (30 intact fibers, 47 injured fibers) and 34 functionally characterized A-fibers (11 intact fibers, 23 injured fibers) were tested for their responses to menthol applied to their receptive fields either in the skin (10% or 20%) or in the nerve (4 or 8 mM). Menthol activated all intact (N=12) and 90% of injured (N=20/22) type 1 cold-sensitive C-fibers; it activated no intact type 2 cold-sensitive C-fiber (N=7) and 1/11 injured type 2 cold-sensitive C-fiber. Neither intact nor injured heat- and/or mechanosensitive cold-insensitive C-fibers (N=25) and almost no A-fibers (N=2/34) were activated by menthol. These results strongly argue that cutaneous type 1 cold-sensitive afferent fibers are non-nociceptive cold fibers that use the TRPM8 transduction channel.Journal of Neurophysiology 02/2014; 111(10). DOI:10.1152/jn.00287.2013 · 3.04 Impact Factor