Enhancement of Ectopic Discharge in Regenerating A- and C-Fibers by Inflammatory Mediators

Physiologisches Institut, Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany.
Journal of Neurophysiology (Impact Factor: 2.89). 04/2009; 101(6):2762-74. DOI: 10.1152/jn.91091.2008
Source: PubMed


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.

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    • "Movement artefacts caused by electrical stimulation of the sciatic nerve were reduced by ligating the peroneal nerve. Consistent with previous studies examining acute nerve lesions, nerve ligation has negligible effects on the physiology of C-fiber axons during the few hours of the experiment (Michaelis et al., 1995; Grossmann et al., 2009; Richards et al., 2011). The L5 dorsal root was teased into fine filaments (6–10-lm diameter), which were placed individually over a gold bipolar recording electrode. "
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    ABSTRACT: Neuritis can cause pain hypersensitivities in the absence of axonal degeneration. Such hypersensitivities are reputed to be maintained by ongoing activity into the spinal cord, which, in the neuritis model, is mainly generated from intact C-fiber neurons. The hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channels has been implicated in nerve injury-induced pain hypersensitivities. The present study has examined the role of these channels in the development of heat and mechanical hypersensitivities in the neuritis model. The systemic administration of the HCN-specific blocker ZD7288 produced a reversal of heat but not mechanical hypersensitivity within one hour post-administration.Recordings from C-fiber neurons were performed to determine whether ZD7288 acts by inhibiting ongoing activity. ZD7288 (0.5 mM) caused a 44.1% decrease in the ongoing activity rate following its application to the neuritis site. Immunohistochemical examination of the HCN2 channel subtype within the L5 dorsal root ganglia revealed an increase in expression in neuronal cell bodies of all sizes post-neuritis. In conclusion, HCN channels contribute to the development of neuritis-induced heat hypersensitivity and ongoing activity. Drugs that target HCN channels may be beneficial in the treatment of neuropathic pain in patients with nerve inflammation.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.08.058 · 3.36 Impact Factor
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    • "In this study we did not measure the strength of the mechanical stimuli applied to the nerve injury site (or the skin), but we did so in previous studies (Grossmann et al. 2009b; Jänig et al. 2009). Strong (noxious) mechanical stimuli were applied to the skin with the use of a forceps (pinch stimuli) or a fine-tipped glass rod (strong pressure stimuli). "
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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 · 2.89 Impact Factor
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    • "Thermal sensitivity was tested qualitatively using a finetipped metal rod (tip diameter 1 mm) of 5 °C or approximately 50 °C. The functional properties of the injured cutaneous nerve fibers have been described recently [34] [35] [38]. The functional properties of the injured muscle nerve fibers are described by Kirillova et al. [45] "
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    ABSTRACT: Lidocaine applied systemically or locally attenuates neuropathic pain in patients. Here we tested the hypothesis that ectopic activity in injured afferent A- or C-fibers is suppressed by lidocaine. In rats the sural nerve (skin nerve) or lateral gastrocnemius-soleus nerve (muscle nerve) was crushed. Four to 11 days after crush lesion afferent fibers were isolated from the lesioned nerves in bundles rostral to the injury site. Ongoing ectopic activity was recorded from 75 A-fibers (muscle N=43, skin N=32) and 69 C-fibers (muscle N=30, skin N=39). Most afferent fibers were functionally characterized by their responses to mechanical and thermal (mostly heat) stimuli applied at or distal to the nerve injury site. Low-threshold cold-sensitive cutaneous C-fibers were excluded from the analysis. Lidocaine was either applied to the nerve at or distal to the injury site in concentrations of 1 to 1000 μg/mL or injected i.v. in doses of 0.09 to 9 mg/kg (skin) or 0.047 to 4.7 mg/kg (muscle). Local application of lidocaine depressed ectopic activity in A- and C-fibers dose-dependently. Depression was weaker in C- than in A-fibers. Intravenous application of lidocaine depressed ongoing ectopic activity in A- and C-fibers dose-dependently. Responses to heat or mechanical stimulation of the injured nerve were not suppressed at the highest concentrations of lidocaine. The results support the hypothesis that decrease of neuropathic pain following local or systemic application of a local anesthetic is related to decrease of ectopic ongoing activity in injured afferent nerve fibers.
    Pain 07/2011; 152(7):1562-71. DOI:10.1016/j.pain.2011.02.046 · 5.21 Impact Factor
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