Cytokine and Chemokine Regulation of Sensory Neuron Function

Molecular Pharmacology and Structural Biochemistry, Northwestern University, Chicago, IL, USA.
Handbook of experimental pharmacology 02/2009; 194(194):417-49. DOI: 10.1007/978-3-540-79090-7_12
Source: PubMed


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.

Download full-text


Available from: Richard J Miller,
  • Source
    • "One increasingly recognized approach to delineate the effects of a systemic immune activation on pain is the experimental administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS). LPS, the major component of the outer membrane of Gram-negative bacteria, is a prototypic pathogen-associated molecular pattern that stimulates via Toll-like receptor (TLR) 4-dependent pathways the synthesis and release of pro-inflammatory cytokines (Bahador and Cross, 2007; Miller et al., 2009; Schedlowski et al., 2014). These pro-inflammatory mediators control local and systemic immune responses to pathogens like LPS, and – more importantly in the context of pain – also have effects on the central nervous system, evoking behavioral, neuroendocrine, and metabolic changes (Bahador and Cross, 2007; Benson et al., 2012a; Dantzer et al., 2008; Schedlowski et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Inflammation-induced pain amplification and hypersensitivity play a role in the pathophysiology of numerous clinical conditions. Experimental endotoxemia has recently been implemented as model to analyze immune-mediated processes in human pain. In this study, we aimed to analyze dose- and time-dependent effects of lipopolysaccharide (LPS) on clinically-relevant pain models for musculoskeletal and neuropathic pain as well as the interaction among LPS-induced changes in inflammatory markers, pain sensitivity and negative affect. Methods: In this randomized, double-blind, placebo-controlled study, healthy male subjects received an intravenous injection of either a moderate dose of LPS (0.8 ng/kg Escherichiacoli), low-dose LPS (0.4 ng/kg), or saline (placebo control group). Pressure pain thresholds (PPT), mechanical pain sensitivity (MPS), and cold pain sensitivity (CP) were assessed before and 1, 3, and 6h post injection to assess time-dependent LPS effects on pain sensitivity. Plasma cytokines (TNF-α, IL-6, IL-8, IL-10) and state anxiety were repeatedly measured before, and 1, 2, 3, 4, and 6h after injection of LPS or placebo. Results: LPS administration induced a systemic immune activation, reflected by significant increases in cytokine levels, body temperature, and negative mood with pronounced effects to the higher LPS dose. Significant decreases of PPTs were observed only 3h after injection of the moderate dose of LPS (0.8 ng/kg). MPS and CP were not affected by LPS-induced immune activation. Correlation analyses revealed that decreased PPTs were associated with peak IL-6 increases and negative mood. Conclusions: Our results revealed widespread increases in musculoskeletal pain sensitivity in response to a moderate dose of LPS (0.8 ng/kg), which correlate both with changes in IL-6 and negative mood. These data extend and refine existing knowledge about immune mechanisms mediating hyperalgesia with implications for the pathophysiology of chronic pain and neuropsychiatric conditions.
    Brain Behavior and Immunity 10/2014; 41(1). DOI:10.1016/j.bbi.2014.05.001 · 5.89 Impact Factor
  • Source
    • "Apart from their expression in glia cells, at least five different chemokines (CCL2, CCL21, CXCL10, CXCL12 and CX3CL1) have been described in neurons in the last few years, predominately under conditions of neuronal stress or injury (de Haas et al., 2007; Biber et al., 2008; Miller et al., 2008). Since these chemokines have electrophysiological effects in neurons (Oh et al., 2002; Callewaere et al., 2006; Guyon et al., 2009; Miller et al., 2009) and control glia cell function in brain pathology (Cardona et al., 2008; Ransohoff, 2009), an important function of these neuronal chemokines in conveying signals from injured neurons has been suggested (de Haas et al., 2007; Ransohoff, 2009). The role of chemokines as microglia instruction signals has gained particular interest in the field of neuropathic pain, where at least three different neuronal chemokines (CX3XL1, CCL2 and CCL21) are playing different roles. "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Cellular Neuroscience 08/2014; 8:210. DOI:10.3389/fncel.2014.00210 · 4.29 Impact Factor
  • Source
    • "In particular, nociceptors may be sensitive to central as well as peripheral inflammatory signals (integrating these with other signals of severe bodily injury, such as retrograde signals from intensely activated postsynaptic neurons, Walters, 2012), and nociceptor activity may in turn stimulate central as well as peripheral inflammatory responses (see below). An implication of these views is that positive feedback loops between enhanced electrical activity in primary nociceptors and combined activation of peripheral and central inflammatory cells may help to sustain neuroinflammation and chronic neuropathic pain (Miller et al., 2009; Walters, 2012; Xie et al., 2009). Support for these views first came from evidence that contusive SCI enhances the growth of uninjured nociceptors distant from a spinal lesion site (Bedi et al., 2012; Hou et al., 2009; Krenz and Weaver, 1998; Ondarza et al., 2003; Ramer et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain.
    Experimental Neurology 08/2014; 258:48–61. DOI:10.1016/j.expneurol.2014.02.001 · 4.70 Impact Factor
Show more