Article

Cytokine and chemokine regulation of sensory neuron function.

Molecular Pharmacology and Structural Biochemistry, Northwestern University, Chicago, IL, USA.
Handbook of experimental pharmacology 02/2009; DOI: 10.1007/978-3-540-79090-7_12
Source: PubMed

ABSTRACT Pain normally subserves a vital role in the survival of the organism, prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role. In conditions of neuropathic pain, spontaneous or hypersensitive pain behavior occurs in the absence of the appropriate stimuli. Our incomplete understanding of the mechanisms underlying chronic pain hypersensitivity accounts for the general ineffectiveness of currently available options for the treatment of chronic pain syndromes. Despite its complex pathophysiological nature, it is clear that neuropathic pain is associated with short- and long-term changes in the excitability of sensory neurons in the dorsal root ganglia (DRG) as well as their central connections. Recent evidence suggests that the upregulated expression of inflammatory cytokines in association with tissue damage or infection triggers the observed hyperexcitability of pain sensory neurons. The actions of inflammatory cytokines synthesized by DRG neurons and associated glial cells, as well as by astrocytes and microglia in the spinal cord, can produce changes in the excitability of nociceptive sensory neurons. These changes include rapid alterations in the properties of ion channels expressed by these neurons, as well as longer-term changes resulting from new gene transcription. In this chapter we review the diverse changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes.

0 Bookmarks
 · 
85 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pain patients who are nicotine dependent report a significantly increased incidence and severity of pain intensity. The goal of this study was to determine the effects of prolonged nicotine administration on inflammatory proteins implicated in the development of peripheral and central sensitization of the trigeminal system. Behavioral, immunohistochemical, and microarray studies were utilized to investigate the effects of nicotine administered daily for 14 days via an Alzet ® osmotic pump. Systemic nicotine administration caused a significant increase in nocifensive withdrawals to mechanical stimulation of trigeminal neurons. Nicotine stimulated expression of the pro-inflammatory signal transduction proteins p-ERK, p-JNK, and PKA in the spinal trigeminal nucleus. Nicotine also promoted elevations in the expression of GFAP, a biomarker of activated astrocytes, and the microglia biomarker Iba1. Similarly, levels of eleven cytokines were significantly elevated with the largest increase in expression of TNF-α. Levels of PKA, p-ERK, and p-JNK in trigeminal ganglion neurons were increased by nicotine. Our findings demonstrate that prolonged systemic administration of nicotine promotes sustained behavioral and cellular changes in the expression of key proteins in the spinal trigeminal nucleus and trigeminal ganglion implicated in the development and maintenance of peripheral and central sensitization. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; DOI:10.1016/j.neuroscience.2015.01.034 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionEpigallocatechin 3-gallate (EGCG), a polyphenol present in green tea, was shown to exert chondroprotective effects in vitro. In this study, we used a post-traumatic osteoarthritis (OA) mouse model to test whether EGCG could slow the progression of OA and relieve OA-associated pain.MethodsC57BL/6 mice were subjected to surgical destabilization of the medial meniscus (DMM) or sham surgery. EGCG (25 mg/kg) or vehicle control was administered daily for four or eight weeks by intraperitoneal injection starting on the day of surgery. OA severity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical analysis to detect cleaved aggrecan and type II collagen, and expression of proteolytic enzymes matrix metalloproteinase (MMP)-13 and A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS5). Real-time polymerase chain reaction (PCR) was performed to characterize the expression of genes critical for articular cartilage homeostasis. During the course of the experiments, tactile sensitivity testing (von Frey test) and open field assays were used to evaluate pain behaviors associated with OA, and expression of pain expression markers and inflammatory cytokines in the dorsal root ganglion (DRG) were determined by real-time PCR.ResultsFour and eight weeks after DMM surgery, the cartilage in EGCG-treated mice exhibited less Safranin O loss and cartilage erosion, and lower OARSI scores compared to vehicle-treated controls, which was associated with reduced staining for aggrecan and type II collagen cleavage epitopes, and reduced staining for MMP-13 and ADAMTS5 in the articular cartilage. Articular cartilage in the EGCG-treated mice also exhibited reduced levels of MMP-1, ¿3, ¿8, ¿13, ADAMTS5, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-¿ mRNA and elevated gene expression of the MMP regulator Cbp/p300 Interacting Transactivator 2 (CITED2). Compared to vehicle controls, mice treated with EGCG exhibited reduced OA-associated pain, as indicated by higher locomotor behavior (i.e. distance traveled). Moreover, expression of chemokine receptor (CCR2), and pro-inflammatory cytokines IL-1ß and TNF-¿ in the DRG were significantly reduced to levels similar to sham-operated animals.Conclusions This study provides the first evidence in an OA animal model that EGCG significantly slows OA disease progression and exerts a palliative effect.
    Arthritis Research & Therapy 12/2014; 16(6):508. DOI:10.1186/s13075-014-0508-y · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chemokines and opioids are important regulators of immune, inflammatory and neuronal responses in peripheral and central pain pathways. Recent studies have provided insights into the functional interactions between chemokine receptors and opioid receptors, and their role in pain modulation. In this Progress article, we discuss how crosstalk between these two systems might provide a molecular and cellular framework for the development of novel analgesic therapies for the management of acute and/or chronic pain.
    Nature reviews. Neuroscience 02/2015; 16(2):69-78. DOI:10.1038/nrn3858 · 31.38 Impact Factor

Full-text (2 Sources)

Download
29 Downloads
Available from
May 21, 2014