Cytokine and chemokine regulation of sensory neuron function

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.

Fig. 1

Nociceptive pathways in the dorsal root ganglia (DRG) and central nervous system. Axons of nociceptors transmit information from the periphery to second-order neurons in the dorsal horn of the spinal cord. Neural connections from the dorsal horn to the thalamus and from there to the cortex relay this noxious information to higher centers of the central nervous system. The central axons of primary afferent nociceptive neurons also provide information to polysynaptic spinal cord interneurons, which are essential for the withdrawal reflex. Descending pathways originating in the cortex and/or midbrain provide modulatory feedback signals at the level of the spinal cord. Impulses can also travel back along the peripheral axon toward the distal nerve endings, resulting in neurogenic inflammation

Fig. 2

The Toll-like receptor (TLR) pathway. TLR activation initiates the innate immune response, which is thought to lead to the detrimental cytokine cascade in chronic pain. Activation of TLR signaling proceeds via a family of adaptor proteins which includes the protein MyD88, the interleukin-1 receptor associated kinase, Toll interacting protein, and the adapter protein TRAF6. These proteins activate the kinase TAK1, which ultimately leads to the activation of signaling cascades including nuclear factor κB and mitogen activated protein kinase (MAPK) pathways. The activation of these pathways can then direct the synthesis of cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Both TLRs and receptors for IL-1β have similar structures and share a cytoplasmic motif. Activation of both types of receptors recruits a scaffolding complex that leads to upregulation of the production of similar cytokines

Fig. 3

Possible molecular mechanisms of TNF-α action. TNF-α produces changes in the behavior of sensory neurons at a variety of levels. While some long-term changes in behavior require alterations in gene transcription and protein expression, TNF-α and other upstream cytokines can produce very rapid changes in neuronal excitability as well. These changes in excitability probably arise from direct effects of cytokine signaling on the properties of important ion channels, including voltage-dependent sodium channels and transient receptor potential (TRP) channels expressed by sensory nerves. Activation of TNF-α receptors (TNFRs) produces a wide array of signaling options beginning with recruitment of TNFR-associated death domain protein, receptor-interacting protein, and TNFR-associated factor 2. These proteins go on to activate extracellular-signal-related kinase/MAPK, p38/MAPK, and NFκB pathways

Fig. 4

Rapid effects of the IL-6 pathway. DRG neurons can express IL-6 under some circumstances, as well as components of the IL-6 receptor complexes, suggesting that it can also produce direct effects on DRG neuron excitability. DRG neurons have been shown to express the glycoprotein 130 cytokine receptor subunit, a common feature of all cytokine receptors in the IL-6 family. IL-6 is able to rapidly sensitize vanilloid 1 (TRPV1) conductances to heat as well as to stimulate calcitonin gene-related peptide release via Janus kinase and protein kinase Cd pathways. It is likely that the binding portion of the IL-6 receptor can be provided in trans

Fig. 5

Injury-induced chemokine expression in DRG. Evidence suggests that prolonged chemokine and chemokine receptor expression in sensory ganglia may be a significant contributor to neuropathic pain syndromes. It is likely that chemokines affect neuronal hyperexcitability by transactivating TRP channels. While proinflammatory cytokines such as TNF-α, IL-6 and prostaglandin E are expressed early on and contribute to the genesis of chronic pain, evidence suggests that chemokines are expressed at later time points and may act as the trigger to convert the acute pain to one that is chronic in nature

Fig. 6

Injury-induced changes in the nociceptive pathway. In neuropathic pain, nociceptive pathways are altered at all levels of the central and peripheral nervous systems. Inflammatory cytokines and chemokines may play a key role in coordinating injury-associated nociceptive events as they regulate the inflammatory response and can simultaneously act upon elements of the nervous system, including the peripheral nerve (a), the DRG (b), and the dorsal horn of the spinal cord (c). Rapid effects of these molecules can alter the excitability of neurons, and the sensitization of ion channels involved in the neuropathic pain mechanism. Slower effects of cytokines include altered gene expression, which could the result in the subsequent upregulation of other proinflammatory cytokines, and ion channel expression. These events, which occur in many different cell types, when taken together result in an altered state of excitability that contributes to the chronic pain state. NGF nerve growth factor, NO nitric oxide, TNF-α tumor necrosis factor α, IL-1β interleukin-1β, TLR Toll-like receptor, ATP adenosine triphosphate, TRPV1 transient receptor potential vanilloid 1, CGRP calcitonin gene-related peptide, IL-6 interleukin-6, CCR2 C-C chemokine receptor 2, CXCR3 C-X-C chemokine receptor 3, CXCR4 C-X-C chemokine receptor 4, MCP-1 monocyte chemotactic protein 1, SDF-1 stromal cell derived factor 1, RANTES regulated upon activation, normal T cell expressed and secreted