Mode of Action of cytokines on nociceptive neurons
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. Experimental Brain Research
(Impact Factor: 2.04).
04/2009; 196(1):67-78. DOI: 10.1007/s00221-009-1755-z
Cytokines are pluripotent soluble proteins secreted by immune and glial cells and are key elements in the induction and maintenance of pain. They are categorized as pro-inflammatory cytokines, which are mostly algesic, and anti-inflammatory cytokines, which have analgesic properties. Progress has been made in understanding the mechanisms underlying the action of cytokines in pain. To date, several direct and indirect pathways are known that link cytokines with nociception or hyperalgesia. Cytokines may act via specific cytokine receptors inducing downstream signal transduction cascades, which then modulate the function of other receptors like the ionotropic glutamate receptor, the transient vanilloid receptors, or sodium channels. This receptor activation, either through amplification of the inflammatory reaction, or through direct modulation of ion channel currents, then results in pain sensation. Following up on results from animal experiments, cytokine profiles have recently been investigated in human pain states. An imbalance of pro- and anti-inflammatory cytokine expression may be of importance for individual pain susceptibility. Individual cytokine profiles may be of diagnostic importance in chronic pain states, and, in the future, might guide the choice of treatment.
Available from: Liping Zhang
- "The remarkable structure is similar to the ''jelly-roll'' motif structure characteristic of viral coat proteins on cellular membranes (Jones et al., 1989). This mechanism was later dismissed with findings that the TNF trimer is tethered to the receptor and that only after interaction with the receptor will it exert its effects (van der Goot et al., 1999; Uceyler et al., 2009). Transmembrane TNFa overexpression is reported in TNFR1/2 KO mice using an inflammatory arthritis model (Edwards et al., 2006). "
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ABSTRACT: Tumor necrosis factor alpha (TNFα) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFα dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFα dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild type and TNFR1/2 KO mice.
Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10 weeks post.
TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10 week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in wild type mice. Proteomic profiling 10 weeks after chronic TIC injury revealed TNFα, IL-1α, IL-5, IL-23, MIP-1β, and GM-CSF were increased more than 2-fold in TNFR1/2 KO mice compared to wild type mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 MAPK inhibitor and microglial inhibitor minocycline reduced hypersensitivity.
The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFα dysregulation. The data support involvement of both neurogenic and humoral influences in chronic neuropathic pain.
Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
Available from: Nurcan Üçeyler
- "Cytokines are pleiotropic small proteins that are key players in the induction and maintenance of neuropathic pain . In several neuropathic pain conditions such as painful neuropathies, complex regional pain syndrome or small fiber neuropathy, an imbalance of systemic or local cytokine profiles has been reported e.g. for pro- and anti-inflammatory interleukins –. "
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Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN.
Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8).
IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar.
While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered.
Available from: Knut Biber
- "Furthermore, it is known that pro-inflammatory cytokines including IL-1β or TNFα also directly affect the signaling and excitability of sensory neurons (see for review: Uçeyler et al., 2009). Moreover, it has been shown that these pro-inflammatory cytokines induce the release of several neuropeptides, such as substance P (SP) or calcitonine gene-related peptide (CGRP) from C fibers, which in turn initiate a higher expression of pain sensing receptors and increased excitability in sensory neurons; a process called neurogenic inflammation (Uçeyler et al., 2009). Thus, the impact of inflammatory factors on the pain sensing system is manifold and yet by far not completely understood. "
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ABSTRACT: The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.
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