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: 2.17). 04/2009; 196(1):67-78. DOI: 10.1007/s00221-009-1755-z
Source: PubMed

ABSTRACT 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.

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    • "Systemic influences have been shown to result from circulating inflammatory mediators (e.g. cytokines) and/or hormones released in response to inflammation or pain (Koltzenburg et al., 1999; Milligan et al., 2003; Uceyler et al., 2009). Thus at least some of these changes seem likely to result from systemic influences. "
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    ABSTRACT: Two pore domain potassium (K2P) channels (KCNKx.x) cause K + leak currents and are major contributors to resting membrane potential. Their roles in dorsal root ganglion (DRG) neurons normally, and in pathological pain models, are poorly understood. Therefore, we examined mRNA levels for 10 K2P channels in L4 and L5 rat DRGs normally, and 1 day and 4 days after unilateral cutaneous inflammation, induced by intradermal complete Freund's adjuvant (CFA) injections. Spontaneous foot lifting (SFL) duration (spontaneous pain behaviour) was measured in 1 day and 4 day rats < 1 h before DRG harvest. mRNA levels for KCNK channels and Kv1.4 relative to GAPDH (n = 4-6 rats/group) were determined with real-time RT-PCR. This study is the first to demonstrate expression of THIK1, THIK2 and TWIK2 mRNA in DRGs. Abundance in normal DRGs was, in descending order:
    Molecular and Cellular Neuroscience 01/2012; 49(3):375-86. DOI:10.1016/j.mcn.2012.01.002 · 3.73 Impact Factor
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    • "(TNF-a), which can enhance nociceptive transmission by activating dorsal horn neurons (Vitkovic et al., 2000; Winkelstein et al., 2001; Watkins and Maier, 2003; Uceyler et al., 2009). Moreover, Xu et al. (2006) reported that TNF-a plays a crucial role in the development and maintenance of neuropathic pain. "
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    ABSTRACT: The investigators previously found that the administration of lemnalol, a natural marine compound isolated from the Formosan soft coral Lemnalia cervicorni, produced anti-inflammatory and analgesic effects in carrageenan-injected rats. Recently, several studies have demonstrated that the development and maintenance of neuropathic pain are accompanied by releasing of proinflammatory mediators from activated glial cells in the spinal cord. In this study, we investigated the antinociceptive properties of lemnalol, a potential anti-inflammatory compound, on chronic constriction injury (CCI) in a well-established rat model of neuropathic pain. Our results demonstrated that a single intrathecal administration of lemnalol (0.05-10 μg) significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, 14 days postsurgery. Furthermore, immunohistofluorescence analyses showed that lemnalol (10 μg) also significantly inhibits CCI-induced upregulation of microglial and astrocytic immunohistochemical activation markers in the dorsal horn of the lumbar spinal cord. Double immunofluorescent staining demonstrated that intrathecal injection of lemnalol (10 μg) markedly inhibited spinal proinflammatory mediator tumor necrosis factor-α expression in microglial cells and astrocytes in neuropathic rats. Collectively, our results indicate that lemnalol is a potential therapeutic agent for neuropathic pain, and that further exploration of the effects of lemnalol on glial proinflammatory responses is warranted.
    Behavioural pharmacology 12/2011; 22(8):739-50. DOI:10.1097/FBP.0b013e32834d0ecb · 2.19 Impact Factor
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    • "he activation of transcription factors such as NF - jB , which induces the expression of a large number of proinflammatory cyto - kines ( Wallach et al . 2002 ) . Therefore , the inter - relation - ships between NGF and inflammatory cytokines are complex and reciprocal ( Cunha & Ferreira , 2003 ; Thacker et al . 2007 ; Spedding & Gressens , 2008 ; Uçeyler et al . 2009 ) ."
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    ABSTRACT: The normal intervertebral disc (IVD) is a poorly innervated organ supplied only by sensory (mainly nociceptive) and postganglionic sympathetic (vasomotor efferents) nerve fibers. Interestingly, upon degeneration, the IVD becomes densely innervated even in regions that in normal conditions lack innervation. This increased innervation has been associated with pain of IVD origin. The mechanisms responsible for nerve growth and hyperinnervation of pathological IVDs have not been fully elucidated. Among the molecules that are presumably involved in this process are some members of the family of neurotrophins (NTs), which are known to have both neurotrophic and neurotropic properties and regulate the density and distribution of nerve fibers in peripheral tissues. NTs and their receptors are expressed in healthy IVDs but much higher levels have been observed in pathological IVDs, thus suggesting a correlation between levels of expression of NTs and density of innervation in IVDs. In addition, NTs also play a role in inflammatory responses and pain transmission by increasing the expression of pain-related peptides and modulating synapses of nociceptive neurons at the spinal cord. This article reviews current knowledge about the innervation of IVDs, NTs and NT receptors, expression of NTs and their receptors in IVDs as well as in the sensory neurons innervating the IVDs, the proinflammatory role of NTs, NTs as nociception regulators, and the potential network of discogenic pain involving NTs.
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