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: 3.3). 04/2009; 101(6):2762-74. DOI: 10.1152/jn.91091.2008
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: After experimental nerve injuries that extensively disrupt axons, such as chronic constriction injury, immune cells invade the nerve, related dorsal root ganglia (DRGs), and spinal cord, leading to hyperexcitability, raised sensitivity, and pain. Entrapment neuropathies, such as carpal tunnel syndrome, involve minimal axon damage, but patients often report widespread symptoms. To understand the underlying pathology, a tube was placed around the sciatic nerve in 8-week-old rats, leading to progressive mild compression as the animals grew. Immunofluorescence was used to examine myelin and axonal integrity, glia, macrophages, and T lymphocytes in the nerve, L5 DRGs, and spinal cord after 12 weeks. Tubes that did not constrict the nerve when applied caused extensive and ongoing loss of myelin, together with compromise of small-, but not large-, diameter axons. Macrophages and T lymphocytes infiltrated the nerve and DRGs. Activated glia proliferated in DRGs but not in spinal cord. Histologic findings were supported by clinical hyperalgesia to blunt pressure and cold allodynia. Tubes that did not compress the nerve induced only minor local inflammation. Thus, progressive mild nerve compression resulted in chronic local and remote immune-mediated inflammation depending on the degree of compression. Such neuroinflammation may explain the widespread symptoms in patients with entrapment neuropathies.
    Journal of neuropathology and experimental neurology. 06/2013;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study was aimed at the issue of whether peripheral nerve injury-induced chronic pain is maintained by supraspinal structures governing descending facilitation to the spinal dorsal horn, or whether altered peripheral nociceptive mechanisms sustain central hyperexcitability and, in turn, neuropathic pain. We examined this question by determining the contribution of peripheral/spinal mechanisms, isolated from supraspinal influence(s), in cutaneous hypersensitivity in an animal model of peripheral neuropathy. Adult rats were spinalized at T8-T9; 8 days later, peripheral neuropathy was induced by implanting a 2-mm polyethylene cuff around the left sciatic nerve. Hind paw withdrawal responses to mechanical or thermal plantar stimulation were evaluated using von Frey filaments or a heat lamp, respectively. Spinalized rats without cuff implantation exhibited a moderate decrease in mechanical withdrawal threshold on ∼day 10 (P < 0.05) and in thermal withdrawal threshold on ∼day 18 (P < 0.05). However, cuff-implanted spinalized rats developed a more rapid and significant decrease in mechanical (∼day 4; P < 0.001) and thermal (∼day 10; P < 0.05) withdrawal thresholds that remained significantly decreased through the duration of the study. Our findings demonstrate an aberrant peripheral/spinal mechanism that induces and maintains thermal and to a greater degree tactile cutaneous hypersensitivity in the cuff model of neuropathic pain, and raise the prospect that altered peripheral/spinal nociceptive mechanisms in humans with peripheral neuropathy may have a pathologically relevant role in both inducing and sustaining neuropathic pain.
    Pain Medicine 07/2013; 14(7):1057-71. · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The diagnosis of entrapment neuropathies can be difficult because symptoms and signs often do not follow textbook descriptions and vary significantly between patients with the same diagnosis. Signs and symptoms which spread outside of the innervation territory of the affected nerve or nerve root are common. This Masterclass provides insight into relevant mechanisms that may account for this extraterritorial spread in patients with entrapment neuropathies, with an emphasis on neuroinflammation at the level of the dorsal root ganglia and spinal cord, as well as changes in subcortical and cortical regions. Furthermore, we describe how clinical tests and technical investigations may identify these mechanisms if interpreted in the context of gain or loss of function. The management of neuropathies also remains challenging. Common treatment strategies such as joint mobilisation, neurodynamic exercises, education, and medications are discussed in terms of their potential to influence certain mechanisms at the site of nerve injury or in the central nervous system. The mechanism-oriented approach for this Masterclass seems warranted given the limitations in the current evidence for the diagnosis and management of entrapment neuropathies.
    Manual therapy 09/2013; · 2.32 Impact Factor


1 Download
Available from
Jul 3, 2014