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Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press; 2010.

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Translational Pain Research: From Mouse to Man.

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Chapter 8Cytokines in Pain

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8.1. INTRODUCTION

The development of insights into the role of cytokine modulation of pain has been the prototypical story of translational research from mouse to man. Pain has been understood in the context of inflammation associated with tissue injury: nociception in a milieu of an inflammatory soup bathing small nerve fibers following tissue injury. Translational research with mice during the past decade has now revealed that the pathogenesis of neuropathic pain, the devastating pain condition associated with direct injury or disease to the somatosensory nervous system, is also a consequence of inflammation of a type described as cytokine-mediated neuroinflammation regulated by glia and neurons.

In this chapter we will review the current understanding of cytokines in the pathogenesis of pain, and especially neuropathic pain, based on basic science research with rodent models of peripheral nerve injury. This knowledge has expanded understanding of the role of cytokines in neural dysfunction and provided an additional rationale for therapeutic use of anti-cytokine agents in human painful degenerative diseases. Herein, we review recent data to support the concept that the proinflammatory cytokine-driven processes of degeneration are at the basis of the neuropathic pain condition, and that anti-cytokine therapy represents a promising approach to treating human neuropathic pain states. Additionally, we suggest that the relationship between cytokines and matrix metalloproteinases can be therapeutically exploited.

8.2. CYTOKINES

The term cytokine originates from the Greek cyto (cell) and kinos (movement). Cytokines are small regulatory proteins that are released in a wide variety of cells to modulate cell–cell interaction and other functions especially important for inflammation and immune responses. Cytokines have pleiotropic activities that can trigger several cellular responses depending on cell type, timing, and molecular environment. They act through a respective receptor (as reviewed below) on the cell of their production in an autocrine mode, a neighboring cell in a paracrine mode, or through direct juxtacrine cell–cell interaction.

Cytokines are clustered into several classes: interleukins (IL), tumor necrosis factors (TNF), interferons (IFN), colony-stimulating factors, transforming growth factors, and chemokines. They are also categorized according to the structural homology of their receptors as class I or class II cytokines (Boulay et al. 2003; Langer et al. 2004). Most ILs, colony-stimulating factors, and IFNs belong to one of these two classes of cytokines and mediate their effects through the Janus kinasesignal transducers and activators of transcription (JAK-STAT) pathway. Three other major cytokine families encompass the IL-1 and TNF family members that activate the nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase signaling pathways, and TGF-β superfamily members that activate signaling proteins of the Smad family. In addition, cytokines are often classified according to their functional ability to contribute to inflammation into proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-12, IL-18, and IFNγ or anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, and TGF-β.

8.3. NOCICEPTION AND NEUROPATHIC PAIN

The Kyoto protocol of the International Association for the Study of Pain (IASP) Basic Pain Terminology (Loeser and Treede 2008) now clearly distinguishes between the terms pain and nociception. Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage,” and nociception is now redefined as “the neural processes of encoding and processing noxious stimuli.” Previously the terms had been used less discriminately. It is now noted that pain is a subjective experience, and nociception is a physiological sensory process. The definition of neuropathic pain remains basically the same: “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” We will explore how nociceptive and neuropathic pain states are both influenced by expression of proinflammatory cytokines.

For the purposes of this discussion discriminating the role of cytokines in nociceptive and neuropathic pain states, we characterize nociceptive pain as having the following qualities:

  • Pain caused by tissue injury
  • Pain that is stimulus evoked
  • Pain mediated by normally quiescent C polymodal nociceptors through DRG and spinal neurons
  • Pain associated with increased neuronal activity through wide dynamicrange (WDR) neurons in the spinal cord
  • Pain that can be managed by opioids

whereas neuropathic pain has the following qualities:

  • Pain caused by injury or disease of the nervous system, but typically by injury to the peripheral nervous system
  • Pain that can be either spontaneous in origin or evoked by minor mechanical stimuli
  • Pain that typically develops in days or months after injury
  • Pain mediated by abnormal firing of C polymodal nociceptors and in many cases by A-beta fibers through sensitized WDR neurons
  • Pain that is often refractory to traditional therapies

Apart from the cognitive and emotional aspects of the pain definitions, the nociceptively mediated pain state is typically associated with tissue injury that produces an acute electrophysiologic discharge in nerve terminals and a subacute response in C-polymodal nerve fibers associated with local inflammation of the damaged tissue. The sensitivity of cutaneous afferent nerve endings to an inflammatory environment was made clear by Kessler et al. (Kessler et al. 1992) when they produced an experimental “inflammatory soup” from a broad mixture of inflammatory mediators consisting of bradykinin, serotonin, prostaglandin E2 (PGE2), and histamine, all at pH 7, to investigate the responsiveness of substance P-conditioned primary afferents. This experimental approach has been widely used in many important studies, such that the role of inflammation has become the hallmark of pain and the single best understood aspect of nociception, the processes of mechanical sensitization of acutely injured nerve fibers (Michaelis et al. 1998) and the enhanced excitability of sensory neurons (Ma et al. 2006) (Figure 8.1). These findings are, in fact, at the heart of the definition of nociception.

FIGURE 8.1. Sciatic nerve following transection injury.

FIGURE 8.1

Sciatic nerve following transection injury. Plastic-embedded section of rat sciatic nerve stained with Methylene Blue Azure II. Note the lack of a defining perineurial sheath surrounding the nerve fibers and the disorganized interstitial structure. This (more...)

What has been less well elaborated is the role of cytokines in the production of the inflammatory soup. It is now known that local expression and upregulation of proinflammatory cytokines such as IL-1β induce cPLA2 and COX-2 mRNA and protein expression and subsequent PGE2 release (Moolwaney and Igwe 2005). These experiments further indicated that p38 MAPK cytokine signaling mechanisms (see below) play a role in IL-1β–mediated PGE2 release. Considering the complex inter-relationship of cytokines, other proinflammatory cytokines can certainly be presumed to be involved in the local generation of inflammatory soup. The interleukins, such as IL-1β and IL-6, in association with TNF-α are complementary and synergistic, and they control many other key inflammatory factors such as inducible nitric oxide synthase mRNA that also plays an important role in nociception (Covey et al. 2000, Myers et al. 2006). However, we believe that TNF-α plays a dominant role, in that it stimulates expression of IL-1β and other cytokines, directly causes nociception, and regulates the process of neural remodeling.

In 1850, Augustus Waller (Stoll et al. 2002) described a pathologic process following nerve transection that included an initial reaction at the site of injury and then degeneration and phagocytosis of myelin and axons distal to the injury. Figure 8.1 depicts a nerve bundle after transection injury. What we now know as Wallerian degeneration is fundamental to neuropathology because it occurs after axonal injury of any type, including crush and severe ischemia. Its mechanisms differ importantly from other diseases with axonal degeneration, primarily the dying-back neuropathies, and with pruning of axons during development; these differences are of intense current interest (Coleman 2005; Koike et al. 2008). We focus on the role of cytokines in Wallerian degeneration because they control the invasion and activity of nonresident, hematogenous macrophages that drive the pathology of Wallerian degeneration and that are so closely related to the development of neuropathic pain and the peak periods of hyperalgesia (Myers et al. 1993). The pathology includes gradual axoplasmic disintegration during which the axolemma fragments and its contents undergo granular dissolution (Sommer et al. 1995). The Schwann cell is activated initially and expresses proinflammatory cytokines while the myelin sheath of the Schwann cell forms lamellar ovoids surrounded by Schwann cell cytoplasm. Schwann cells may phagocytose myelin debris, but hematogenous macrophages reinforce and then dominate the process of degeneration and phagocytosis, and are effectively required for Wallerian degeneration (George et al. 1995).

The mechanisms by which macrophages potentiate Wallerian degeneration are not completely understood, although cytokine signaling and secretion of proteases, such as the matrix metalloproteinases (MMPs), play a central role. Following upregulation of proinflammatory cytokines stimulating expression of endothelial adhesion molecules (Beuche and Friede 1984; Stoll et al. 2002), macrophages migrate through the endothelium following additional cytokine and other chemotactic gradients present in injured nerve. Activated macrophages secrete components of the complement cascade, coagulation factors, proteases, hydrolases, interferons, TNF-α, and other cytokines, which facilitate the degeneration and phagocytosis of the nerve fiber. The activation of macrophages may be related to cytokines expressed by activated Schwann cells, mast cells, and endothelial cells following local MMP-induced changes in TNF-α form. Liefner et al. (2000) have used TNF-α gene knockout mice to demonstrate that the main function of TNF-α during Wallerian degeneration is the induction of macrophage recruitment from circulation.

Our previous work shows a progression in neuropathological change related to TNF-α dose. At low doses of TNF-α injected in rat sciatic nerve, there is substantial endoneurial edema accumulating in the subperineurial, perivascular, and endoneurial spaces of the nerve bundle (Wagner and Myers 1996a). At doses in the range of 10 microliters of a 2.5 pg/ml solution of murine recombinant TNF-α, extensive demyelination was observed along the injection tract. Studies of tissue injected with a higher dose of TNF-α showed extensive splitting of myelin lamellae, which formed large vacuoles prior to demyelination. Schwann cells were activated and contained lipid debris consistent with their phagocytic role and macrophages invaded the tissue after 3 days to reinforce the phagocytic process. Activated fibroblasts were present in the endoneurium, and there were reactive changes in endothelial cells. Occasional axons were undergoing Wallerian-like degeneration.

Some normal Schwann cells constitutively express TNF-α and IL-1β in vivo, and there is a significant increase in immunoreactivity during Wallerian degeneration (Wagner and Myers 1996). Documented by immunohistochemistry staining for TNF-α protein and in situ hybridization for TNF-α mRNA, there is an increase in the number and density of Schwann cell cytoplasmic staining for both TNF-α protein and mRNA following nerve injury. Other endoneurial cells immunopositive for TNF-α and IL-1β that are activated during Wallerian degeneration include endothelial cells, fibroblasts, mast cells, and macrophages (Figure 8.2). The initial increase in TNF-α immunoreactivity in endoneurial cells also positive for IL-1β present within hours after nerve injury and is doubled by 7 days. It is thought that the initial increase in Schwann cell proinflammatory cytokine immunoreactivity following nerve injury serves several important functions, including recruitment and activation of macrophages to the injury site and facilitation of the phagocytic role of Schwann cells. The phagocytic process is then extended and amplified by recruited macrophages, which may, in turn, attack Schwann cells. Thus, it is of particular relevance that TNF-α is an active component of nucleus pulposus in herniated lumbar disc tissue (Olmarker and Larsson 1998) and that the related clinical problem of sciatica might be treated by anti-cytokine therapy (see below).

FIGURE 8.2. TNF-α immunoreactivity in damaged nerve.

FIGURE 8.2

TNF-α immunoreactivity in damaged nerve. Light micrograph of frozen section of rat sciatic nerve shortly after chronic constriction injury. Note cellular staining by TNF-α antibody in both epineurial and endoneurial compartments. Dense (more...)

In fact, it is now clearly understood that interfering with the time-course and magnitude of Wallerian degeneration by altering macrophage activity and/or TNF-α expression can modulate the pain experience (Myers et al. 1996; Sommer et al. 2001). This was first demonstrated in experiments with a mouse model of neuropathic pain. Prior to 1996, experimental models of neuropathic pain following nerve injury were conducted primarily in rats using several quantitative measures of pain behavior, such as the Hargreaves test of thermal hyperalgesia (Hargreaves et al. 1988). We adapted these techniques to a mouse model of chronic constriction nerve injury (CCI) using the Wlds(slow Wallerian degeneration) strain of mice to test the hypothesis that a delay in macrophage recruitment would be reflected in a delayed onset and reduced magnitude of the thermal hyperalgesia behavior that is characteristic of the CCI model of neuropathic pain. The hypothesis was initially supported by quantitative measures of macrophage numbers and the rate of Wallerian degeneration, as is inferred by the pathological analysis of the histology in Figure 8.3. Subsequent molecular studies and cytokine analyses have reinforced the hypothesis (Shubayev et al. 2006).

FIGURE 8.3. Delayed Wallerian degeneration of Wldsmice.

FIGURE 8.3

Delayed Wallerian degeneration of Wldsmice. Histological sections (plastic embedded) of peripheral nerve were compared from wild-type (WT) and Wlds animals at days 3, 7, and 28 post-injury to verify that Wallerian degeneration had been delayed in the (more...)

The use of the Wlds mouse for these studies and other fundamental studies of nerve degeneration typifies the importance of translational research. The Wldsmouse has provided insights into neurological degeneration caused by Alzheimer’s disease, Parkinson’s disease, Creutzfeld-Jakob disease, HIV dementia, and multiple sclerosis (Coleman 2005). The Wldsmouse is a spontaneous mutant on chromosome 4 (Lyon et al. 1993) identified as an 85-kb tandem triplication (Coleman et al. 1998) producing a neuroprotective fusion protein of ubiquitin assembly factor E4B (Ube4b) and mononucleotide adenylyltransferase (Nmnat) (Conforti et al. 2000). This genetic defect is intrinsic to neurons causing delay in Wallerian degeneration and, as a result, delay in macrophage migration (Lunn et al. 1989; Perry et al. 1990a, b).

8.4. CYTOKINES IN CENTRAL NEUROINFLAMMATION AND GLIAL ACTIVATION

Persistent and recurring exposure of injured sensory axons to proinflammatory cytokines by activated stimulation of glia and immune cells promotes recurrent ectopic depolarization and leads to spinal sensitization and enhanced painful behavior. This mechanism occurs not only at the site of injury but in the segmental dorsal root ganglia (DRG) and spinal cord (Milligan and Watkins 2009; Scholz and Woolf 2007).

In the DRG, resident macrophages are normally present, alongside satellite “glia,” and though remote from the lesion site, they react to nerve injury by releasing cytokines that foster the influx of infiltrating macrophages (Scholz and Woolf 2007). A week after nerve transection, macrophages are diffused throughout the DRG, where they remain elevated for at least 3 months surrounding the cell bodies of reactive sensory neurons (Hu and McLachlan 2003; Tandrup et al. 2000). The mechanisms of remote neuroinflammation in DRG well after the inflammatory reaction at the nerve lesion site subsides are still not clear, but continuous apoptosis of sensory DRG neurons, resulting in more than 50% neuronal loss by one month after mouse nerve transection, is believed to replenish the proinflammatory cytokine milieu in DRG and contribute to the sustained influx of immune cells (Scholz and Woolf 2007). Proinflammatory cytokines then directly elicit ectopic action potential discharges (see below) and alter the phenotype of sensory neurons, altering the efficacy of their synaptic input into the spinal cord and promoting neuropathic activity (Scholz and Woolf 2007).

Activation of spinal cord glia is both necessary and sometimes even sufficient to the development of persistent pain states associated with various etiologies, including diabetic neuropathy, chemotherapy-induced neuropathy, peripheral nerve inflammation and trauma, and spinal cord inflammation (DeLeo and Winkelstein 2002; Watkins et al. 2007; Wieseler-Frank et al. 2004). Both spinal astrocytes and microglia activate mitogen-activated protein kinases (MAPKs) to induce the synthesis and release of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, PGE2, and nitric oxide (NO) (Ji and Suter 2007; Zhuang et al. 2005). Resident microglia act as a first line of defense to proinflammatory stimuli, which rapidly proliferate to produce inflammatory and anti-inflammatory cytokines and other substances, and to activate nearby astrocytes, microglia, and neurons (Romero-Sandoval et al. 2008). During chronic neuropathic conditions, sustained activation of astrocytes is believed to explain the ongoing activity of neuropathic cascades (Ji and Suter 2007). In addition, astrocytes encapsulate synapses and remain in close contact with neuronal soma where they can directly alter neuronal communication via expression of neurotransmitter receptors, such as ionotropic non-N-methyl-D-aspartic acid (NMDA) and NMDA receptors, metabotropic glutamate, purinergic and substance P receptors (Haydon 2001; Porter and McCarthy 1997). Differential action of MMPs on continuous IL-1β release in microglia and astrocytes is believed to contribute to the development and the maintenance of neuropathic pain (Kawasaki et al. 2008; Myers et al. 2006), as discussed below.

8.5. AXONAL TRANSPORT OF CYTOKINES

The development of pain states is characterized by acute stimulation of the injured sensory axis through electrophysiological stimuli, synaptic release of neurotransmitters, and kinase activity, followed by longer term modulation through gene expression at the injury site and neuronal soma of DRG, in part as a function of retrograde axonal flow (Myers et al. 2006). The importance of injury-induced factors in stimulation of ectopic hyperexcitability of neuronal soma has been demonstrated through the injection of injured axoplasm into the cell bodies of uninjured sensory neurons (Ambron et al. 1995). This neuronal hyperexcitability was diminished with exposure of injured nerves to colchicine, a blocker of axonal transport (Gunstream et al. 1995). Axonal transport of small proteins to the cell body (retrograde) influences cell function and from the cell body (anterograde) influences axon viability (Kristensson 1984; Redshaw and Bisby 1984, 1987). Disruption of bi-directional axonal transport of trophic factors, referred to as “trophic currencies” (Altar and DiStefano 1998; von Bartheld 2004), is considered to be an early and perhaps causative event in many neurodegenerative pathologies (De Vos et al. 2008).

We hypothesized that retrograde axonal transport of proinflammatory cytokines contributes to the pathogenesis of neuropathic pain and have studied this mechanism in the model of peripheral neuropathic pain of rat sciatic nerve chronic constriction injury (CCI) (Schafers et al. 2002; Shubayev and Myers 2001, 2002a). Endogenous TNF-α transport was activated within one day of nerve damage and returned to basal levels within a week of CCI (Shubayev and Myers 2001), a typical temporal pattern for axonal transport of trophic factors after nerve injury (Curtis et al. 1998; Leitner et al. 1999; Tonra et al. 1998). To characterize the speed, direction, and other features of axonal TNF-α transport, we used a biotinylated TNF-α tracer, which was injected at the nerve injury site or directly into neuronal soma of DRG and traced along the sensory nerve tract. TNF-α transported axonally at about 300 mm/day, a speed characteristic of small protein retrograde transport. To compare the specific features of biotin-mediated and biotinylated TNF-α-mediated transport, we used NeurobiotinTM, an amino derivative of biotin (N-(2-aminoethyl)biotinamide) used for intracellular labeling and neuronal tracing studies (Kita and Armstrong 1991). Through a series of studies, we identified the following unique characteristics of TNF-α transport (Shubayev et al. 2005; Shubayev and Myers 2001, 2002a): (1) intraaxonal TNF-α uptake and transport was selective to a subset of fibers, whereas neurobiotin was internalized by all visible fibers; (2) TNF-α tracer localized intraaxonally and in association with the myelin sheath and/or Schwann cell cytoplasm, whereas neurobiotin was found exclusively intraaxonally; (3) upon its retrograde transport along sensory afferents, TNF-α uptake by DRG soma was only observed in uninjured nerve. In injured afferents, TNF-α tracer accumulated in the axons adjacent to neuronal soma of DRG; in contrast, neurobiotin labeled comparably neuronal soma of injured or normal nerve; (4) TNF-α tracer injected into DRG transported anterogradely back to peripheral nerve and to the spinal cord after peripheral nerve injury and in uninjured neuroaxis, similarly to neurobiotin. However, only TNF-α tracer, and only after injection into injured peripheral nerve, reached the segmental spinal cord, implicating the importance of injury-induced factors in TNF-α transport; (5) endogenously expressed TNF-α receptors I and II were found to co-localize with the TNF-α tracer, suggesting that TNF-α transport is receptor mediated; (6) TNF-α tracer co-localized with both calcitonin gene-related peptide (CRPR)-positive and NF200-positive fibers of the ipsilateral spinal cord, and induced activation of spinal glia consistent with its role in the development of neuropathic pain.

Long axonal processes of neurons necessitate efficient means of axonal transport of small proteins, achieved via different cargo systems (De Vos et al. 2008). Cytokinerelated signaling molecules, including MAPKs and JNK (see below), undergo axonal transport (Cavalli et al. 2005); however, future studies need to identify whether and how generation of cytokine signaling endosome occurs (Cosker et al. 2008). Overall, axonal cytokine transport represents a valid mechanism that explains central glial activation and remote neuroinflammation and transcriptional activation of cytokinedependent factors in the generation of persistent pain states (DeLeo and Winkelstein 2002; Watkins and Maier 2002), including phantom and mirror-image pain.

8.6. CYTOKINES AND PAIN SIGNALING

8.6.1. Cytokine-Dependent Intracellular Signaling

Each cytokine has one or more cell-surface receptors that ensure their autocrine, paracrine, or endocrine signaling to phosphorylation of mitogen-activated protein kinases (MAPKs) and regulation of various cellular activities in the neuronal system, such as gene expression, mitosis, differentiation, and cell survival/apoptosis. Studies with knockout mice for proinflammatory cytokine receptor genes have been useful in exploring their specific signaling roles in the development of pain states. For instance, using TNFRI-/- and TNFRII-/- mice have shown that thermal hyperalgesia requires TNFRI, while mechanical and cold allodynia depend on TNFRI or TNFRII (George et al. 2005; Vogel et al. 2006).

Activation of TNF-α receptors and recruitment of TNF-α receptor-associated factors (TRAFs), an important group of intracellular adaptor proteins, leads to phosphorylation of p38 MAPK, extracellular signal-regulated kinases (ERK), and Jun N-terminal kinase (JNK), potentially activating the NF-κB transcription pathways. The complexity of cytokine cross-talk and cytokine signaling can be illustrated, as shown in Figure 8.4. Peripheral nerve injury increases phosphorylation of p38, ERK, and JNK in neurons and non-neuronal cells (e.g., satellite cells) in the DRG (Jin et al. 2003; Kenney and Kocsis 1998; Obata et al. 2003). In addition, nerve injury– induced spinal microglial activation is characterized by phosphorylation of p38 MAP kinase, ERK isoforms 1 and 2 (Jin et al. 2003; Svensson et al. 2005; Zhuang et al. 2005).

FIGURE 8.4. Mechanisms of TNF-α signaling in injured nerve.

FIGURE 8.4

Mechanisms of TNF-α signaling in injured nerve. By occupying either of the two TNF-α receptors, the soluble TNF-α protein can produce different effects ranging from apoptosis to up-regulation of itself, other proinflammatory cytokines, (more...)

In 1994, p38 was first identified as a MAPK targeted by endotoxin and hyperosmolarity in mammalian cells (Han et al. 1994). At the same time, the cloned target for an anti-inflammatory drug (SB203580) was found to be identical to p38 (Lee et al. 1994). It is now known that the regulation of cytokine biosynthesis in many different cell types is mediated through p38 activation. The p38 pathway phosphorylates and enhances the activity of many transcription factors, such as ELK-1, NF-κB, heat shock transcription factor-1, and SAP-1. Activation of p38 in spinal microglia peaks 3 days after peripheral nerve injury, followed by a slow decline over several weeks (Jin et al. 2003). Intrathecal administration of p38 MAPK inhibitors has been demonstrated to inhibit the development of allodynia and hyperalgesia in several models of pain, presumably by blocking p38 phosphorylation in spinal microglia (Ji et al. 2002; Jin et al. 2003; Milligan et al. 2003; Svensson et al. 2003). Although effective in preventing enhanced pain responses, most p38 inhibition has failed to reverse established pain states (Svensson et al. 2003). However, Cytokine Pharmascience’s p38 inhibitor (CNI-1493), administered intrathecally, has been reported to prevent and reverse allodynia associated with extraneural inflammation (Milligan et al. 2003).

ERK was originally identified as a primary effector of growth factor receptor signaling, a cascade that involves sequential activation of Ras, Raf, MEK, and ERK (Ji et al. 2008). Activation of ERK in spinal cord dorsal horn neurons is associated with the activation of nociceptive-specific sensory fibers and promotes intracellular events that contribute to central sensitization, which can manifest at both behavioral and cellular levels (Woolf and Salter 2000). Several studies have shown sequential activation of ERK in dorsal horn neurons, then microglia, and finally astrocytes in a neuropathic pain model (Cheng et al. 2003; Ma and Quirion 2002; Zhuang et al. 2005). Intrathecal MEK inhibitor PD98059 has been demonstrated to attenuate spinal nerve ligation-induced mechanical allodynia (Zhuang et al. 2005). ERK activation is also induced in spinal microglia after streptozotocin (STZ)-induced diabetes, and intrathecal U0126 can suppress STZ-induced neuropathic pain (Tsuda et al. 2008). In addition to peripheral nerve injury, spinal cord injury also activates ERK in spinal microglia, and PD98059 reduces neuropathic pain after spinal cord injury (Zhao et al. 2007). Further, PD98059 inhibits the induction of cyclooxygenase-2 in spinal microglia and spinal release of prostaglandin E2 (Zhao et al. 2007). Collectively, the studies described above indicate that ERK activation in the spinal cord plays an important role in the development and maintenance of neuropathic pain.

Compared with p38 and ERK, little is known about how JNK regulates neuropathic pain. Unlike the activation patterns of ERK and p38, increased phosphorylation of JNK is primarily observed in spinal cord astrocytes at later stages of nerve injury (Zhuang et al. 2005). Intrathecal infusion of the JNK inhibitor SP600125 attenuates neuropathic pain in the SNL model (Obata et al. 2004; Zhuang et al. 2006) and diabetic neuropathy model (Daulhac et al. 2006). Although TNF-α only induces a transient activation of JNK in astrocytes (Zhang et al. 1996), the growth factor FGF-2 (fibroblast growth factor-2) can induce persistent JNK activation in the spinal cord in vivo and in astrocytes in vitro (Ji et al. 2006).

8.6.2. Extracellular Cytokine-Protease Network

Cytokines exist in a variety of biologically active isoforms that allow for a well-coordinated, complex, and self-sustained network. For example, TNF-α is synthesized as a monomeric transmembrane 26 kDa protein that is inserted into a cell membrane as a homotrimer (Wajant et al. 2003) and proteolytically cleaved into a 51 kDa homotrimer by an extracellular metalloprotease of a disintegrin and metalloproteinase (ADAMs) family, TNF-α trimer converting enzyme (TACE or ADAM-17) (Black et al. 1997). Extracellular processing of TNF-α into a dimer, a monomer, and smaller peptides is performed by several members of the extracellular matrix metalloproteinase (MMP) family (Gearing et al. 1994). But the relationship of TNF-α with MMPs is multi-fold and far more complex than merely release of an activated TNF-α ligand. Because proinflammatory cytokines, including TNF-α, are potent inducers of MMP gene expression in various cells (Nagase 1997; Saren et al. 1996), including peripheral glia (Chattopadhyay et al. 2007; Shubayev et al. 2006), TNF-α increases the expression of MMPs to facilitate degradation of neurovascular barriers and infiltration of inflammatory cells (Kieseier et al. 2006; Rosenberg 2002; Shubayev et al. 2006). Therefore, direct injection of exogenous recombinant MMP-9 into the injured nerves of macrophage-deficient TNF-α knockout mice resumed their deficient ability to recruit hematogenous macrophages (Shubayev et al. 2006). Through the use of TNF-α receptors knockout mice, we found that TNFRI and TNFRII are partially responsible for MMP-9 induction in injured sciatic nerve and that other proinflammatory cytokines contribute (Chattopadhyay et al. 2007). At the same time, multiple MMPs regulate TNF-α signaling through processing of TNF-α ligand, leading to activation of TNF-α-dependent signaling and its surface receptors (leading to inactivation), TNFRI and TNFRII (Williams et al. 1996), generating a soluble receptor that can act as a direct TNF-α antagonist, as reviewed further.

MMPs represent a large family of highly potent extracellular proteases that comprise collagenases, stromelysins, gelatinases, and membrane-type (MT)-MMPs (Page-McCaw et al. 2007). In injured peripheral nerve, MMPs control the integrity of blood–brain barrier, myelin protein turnover, survival, and phenotypic remodeling of glia and neurons as summarized in Figure 8.5 (Chattopadhyay et al. 2007; Kobayashi et al. 2008; Shubayev et al. 2006). The specific role of MMPs in generation of pain states is believed to relate to their control of cytokine release (Kawasaki et al. 2008; Myers et al. 2006) as well as myelin protein processing on mechanosensory Aβ fibers (Kobayashi et al. 2008). As an early-gene MMP family member, MMP-9 participates in the initiation of the neuropathic pain state through the immediate changes at the injury site and activation of spinal microglia, whereas a late-gene family member, MMP-2, facilitates the development and the maintenance of neuropathic pain via sustaining activation of spinal astrocytes (Kawasaki et al. 2008; Kobayashi et al. 2008).

FIGURE 8.5. A proposed diagram of cytokine-metalloprotease network in pain processing.

FIGURE 8.5

A proposed diagram of cytokine-metalloprotease network in pain processing. (1) Proinflammatory cytokines induce the expression of the early-gene MMPs, such as MMP-9, in myelinated Schwann cell (Sc) within 1 day after injury. (2) MMPs mediate TNF-α-induced (more...)

Pharmacologic inhibition of MMPs using synthetic hydroxamate-based MMP inhibitors (MMPi) has been considered an important therapeutic approach to cytokine-related neuropathic pain states (Myers et al. 2006). Administration of a broad-spectrum MMP inhibitor or small interfering RNA (siRNA) for MMP-9 and MMP-2 produced an immediate and sustained attenuation of mechanical allodynia (Kawasaki et al. 2008; Kobayashi et al. 2008). Mutant mice with MT5-MMP gene deletion failed to develop mechanical allodynia after partial sciatic nerve ligation (Komori et al. 2004) and MMP-9 knockout mice showed reduced spontaneous pain scores after nerve crush (Chattopadhyay et al. 2007). Little is known about the mechanisms of TACE action in damaged nerve, but its expression and distribution patterns parallel that of TNF-α in CCI-injured sciatic nerve (Shubayev and Myers 2002). Synthetic inhibitor of TACE, TAPI, attenuated mechanical allodynia, and thermal hyperalgesia of CCI (Sommer et al. 1997). It is important to note that hyperalgesia caused by tissue injury resulting from intraplantar endotoxin also responds to MMPi pre-treatment (Talhouk et al. 2000), implicating MMPs in the development of inflammatory pain states. The anti-nociceptive action of minocycline, a broad-spectrum antimicrobial tetracycline that has shown promise in treating persistent pain, is believed to relate to selective inhibition of microglial activation and reduced expression of proinflammatory cytokines and MMPs (Ledeboer et al. 2005; Raghavendra et al. 2003)

8.6.3. Cytokines in Direct Neuronal Excitability

There is an increasing appreciation for the ability of cytokines to directly impact excitatory neuronal function, resulting in spontaneous (ectopic) activity and pain facilitation (Schafers and Sorkin 2008; Scholz and Woolf 2007). For example, application of TNF-α perineurially rapidly evokes ongoing activity in C fibers by reducing mechanical activation thresholds in C nociceptors of sciatic nerve (Junger and Sorkin 2000; Sorkin et al. 1997), and its application to DRG neurons elicits neuronal discharges in A- and C-fibers (Ozaktay et al. 2006; Schafers et al. 2003; Zhang et al. 2002). Dorsal root exposure to TNF-α evoked spontaneous discharges in dorsal horn wide dynamic–range neurons (Onda et al. 2002), and its intrathecal administration enhances responses to C fiber stimulation and increases wind-up and the post-discharge response of deep dorsal horn neurons (Reeve et al. 2000). Intraplantar, DRG, or dorsal root exposure to IL-1β induces spontaneous acute discharges and hyperalgesia, potentiates heat-activated inward currents, or increases mechanosensitivity of the peripheral receptive fields (Fukuoka et al. 1994; Ozaktay et al. 2002). Understanding of the mechanism of cytokine action on neuronal excitability specifically in pain processing is only emerging. Overall, cytokine action on neuronal excitability is believed to relate to their action on ion channels and be (1) acute (within seconds or minutes), modulating post-translational modifications and immediate activity of ion channels subunits, or (2) sustained, modulating gene expression of ion channel proteins.

Ion channels are integral gated pore-forming cell membrane proteins that permit ions to flow down their electrochemical gradients into or out of a cell, referred to as gating. Gating involves a conformational change of one or more subunits and varies depending on the stimuli and the type of a channel. Voltage-gated sodium, calcium, potassium, and transient receptor potential (TRP) channels respond to a difference in electrical membrane potential, as ligand-gated ionotropic channels, such as nicotinic acetylcholine receptor, glutamate-gated N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (APMA) receptors, the anionpermeable α-aminobutyric acid (GABA)A-gated receptor or purinergic ATP-gated P2X receptors, are all stimulated by respective ligands.

Cytokine-stimulated activation of MAPKs promoted phosphorylation of channel subunits, leading to a conformational change affecting their stabilization. In DRG neurons, tetrodotoxin-resistant Na+ currents were controlled by rapid TNF-α/TRNRI-induced activation of p38 MAPK (Jin and Gereau 2006). TNF-α increased the cell surface levels of AMPA receptor via TNFR1-mediated PI3K activation (Stellwagen et al. 2005). AMPA receptor subunit GluR1 was most responsive to TNF-α, resulting in rapid insertion of Ca2+-permeable AMPA channels (Beattie et al. 2002; Ogoshi et al. 2005; Yang et al. 2005). IL-1β can reduce the frequency of AMPA-dependent spontaneous excitatory postsynaptic currents (Yang et al. 2005) and enhance NMDAR-mediated current (Viviani et al. 2003; Yang et al. 2005). Brief IL-1β application sensitized TRPV1 currents (Obreja et al. 2002) and inhibited Na+ currents via IL-1β receptor, whereas its extended exposure increased total Na+ current via the PKC and G-protein-coupled signaling pathway (Liu et al. 2006). TNF-α and IL-1β can acutely reduce the outward K+ and/or inward Na+ current in neurons (Diem et al. 2001; Houzen et al. 1997; Sawada et al. 1991). However, IL-1β and not other tested cytokines rapidly inhibited neuronal activity of voltage-dependent calcium channels by reducing the expression of Ca2+ channel protein (Plata-Salaman and Ffrench-Mullen 1992, 1994; Zhou et al. 2006). These changes impact a variety of mechanisms, including neurotransmitter release (Murray et al. 1997; Rada et al. 1991), long-term potentiation (Cunningham et al. 1996; Katsuki et al. 1990; Schneider et al. 1998), and synaptic transmission (D’Arcangelo et al. 1997). TNF-α can reduce the expression of glutamate EAAT2/GLT-1 transporter (Sitcheran et al. 2005) and IL-1β decreases the expression of Na+ channel subunits in epithelial cells (Choi et al. 2007; Roux et al. 2005). It is not only neuronal, but glia-released cytokines also contribute to neuronal excitability. For example, TNF-α can regulate synaptic scaling via the changes in AMPA receptor subtype density (Stellwagen and Malenka 2006) and can reduce PKC-dependent K+ conductance, affecting glial capacity to buffer extracellular K+ released via neuronal firing (Koller et al. 1998).

Overall, our understanding of the mechanisms of cytokine action on ectopic neuronal excitability in generating pain states is only emerging. But from other models of neuronal excitability, we have learned that cytokines regulate the acute and long-term changes in voltage-gated and ligand-gated ion channels through modulation of their expression levels, conformational changes, and compartmentalization, such as endocytosis of GABA receptor and glutamate uptake by glial transporters.

8.7. CYTOKINE-RELATED THERAPEUTICS

A strong case can be made for the use of anti-TNF-α therapy in painful inflammatory diseases. Indeed, the FDA has approved several anti-TNF-α drugs for use in arthritis, and there is considerable interest in expanding the indications for anti-TNF-α therapy. In particular, the use of anti-TNF-α drugs to treat the pain and neuropathological consequences of herniated discs and sciatica is already undergoing formal clinical study in Europe, and off-label use of anti-TNF-α drugs for sciatica has begun in the United States. The purpose of this section is to review the indications for the use of anti-TNF-α therapy to treat painful neuropathic conditions.

The commercial development of specific soluble TNF-α receptors has greatly advanced the field (Schafers and Sommer 2007). These biologics provide an excess of soluble TNF-α receptors that can occupy the biologically active TNF-α protein before it encounters the receptors on the cell surface. By doing this they effectively neutralize the TNF-α protein in tissue, and therefore reduce its biologic effect. These biologics typically consist of recombinant human tumor necrosis factor p75 TNF-α receptor-Fc fusion protein. Effectively, this provides a therapeutic counter-effect to TNF-α itself. The products are made by encoding the DNA of the soluble portion of human tumor necrosis factor receptor p75 and combining it with the DNA encoded Fc portion of immunoglobulin IgG, translating it to act as an immunoglobulin-like dimer that competitively inhibits TNF-α and prevents its binding to cell surface receptors. Therefore, by binding to the soluble receptor, it reduces the effect of circulating TNF-α. The therapeutic use of the soluble receptor is restricted because the half-life of the molecule is short, and thus combinations of the soluble receptor with immunoglobulin or other molecules has been attempted to try and increase the half life to enable therapeutic applications. Several drugs are now commercially available including the following:

  • etanercept (Enbrel), which has been widely used in rheumatoid arthritis but is also approved for ankylosing spondylitis, psoriasis, and psoriatic arthritis. It is being used off-label for low back pain and other neuroinflammatory diseases (Tobinick 2009).
  • infliximab (Remicade), which is a chimeric monoclonal TNF-α antibody approved for rheumatoid arthritis with methotrexate and for Crohn’s disease. It is currently undergoing formal double-blind, randomized clinical trials for sciatica and has been studied extensively in laboratory animals with experimental spinal disc herniation.
  • adalimumab (Humira) is the newest TNF-α biological response modifier to be approved in the United States and is a fully human recombinant immunoglobulin G1 anti-TNF-α monoclonal antibody.
Several other similar anti-TNF-α biologics are under development.

The rationale for the use of these compounds in human disease comes directly from experimental knowledge of the role of TNF-α in painful radicular neuropathy and from case reports and small clinical trials, particularly with respect to the prevalent problem of lumbar and cervical radiculopathy. Lifetime incidence of lumbar radiculopathy (sciatica) is 20%–40% (Nachemson 2004). Radicular pain is intense, unremitting, and often unresponsive to analgesics. When physical therapy and non-steroidal anti-inflammatory drugs (NSAIDs) provide inadequate relief, treatment progresses to opioid analgesics and to more invasive, expensive measures such as epidural injections of steroids or of local anesthetics. Even these measures are often inadequate in the degree and/or durability of pain relief provided. For patients with MRI-confirmed disc herniation and persistent radicular pain of 6 to 8 weeks’ duration, evaluation for lumbar disc surgery is usually recommended. Natural history studies and randomized controlled trials confirm that more than 50% of first-episode radiculopathy patients recover without surgery if they can obtain adequate pain relief during the initial 2- to 3-month recovery period. Therefore, the decision of whether to elect surgery is often difficult. Indeed, 56% of patients offered surgery declined after viewing a balanced summary of the risks, benefits, and alternatives (Weinstein et al. 2006). Many patients strongly prefer to postpone or avoid lumbar disc surgery, in order to allow spontaneous disc resorption and recovery from disability and pain. Surgeons and patients are actively seeking more effective approaches to relief of radicular pain that are less expensive, less invasive, and more reversible than lumbar disc surgery. Anti-cytokine therapy is therefore actively being explored.

The potential of TNF-α as a target for neuropathic pain therapy is based upon its critical role in mediating neuroinflammation. Of particular importance is the relationship of upregulated TNF-α to spontaneous electrophysiological activity in pain fibers and the process of Wallerian degeneration discussed above, since axonal injury underlies the pathophysiology of radicular pain.

Data from multiple pre-clinical models support the potential of TNF-α inhibition to treat the pain and disability of disc injury by addressing its pathophysiology (Cooper and Freemont 2004; Myers et al. 2006; Olmarker et al. 2004). In the pig nucleus pulposus puncture model, selective TNF-α inhibition protects against nerve root injury, preventing thrombus formation, intraneural edema, and reduced nerve conduction velocity (reviewed by Olmarker et al. 2004, 2005). Similarly, TNF-α inhibition protects from peripheral neuropathy and pain (Schafers et al. 2001). For example, etanercept reduces hyperalgesia in experimental painful neuropathy (Sommer et al. 2001).

TNF-α inhibitors have shown to be of potential efficacy in small academic trials in radiculopathy patients (Karppinen et al. 2003; Korhonen et al. 2004, 2005, 2006; Shin et al. 2006; Tobinick and Davoodifar 2004). A blinded randomized, controlled trial of epidural etanercept has been initiated in patients with MRI-confirmed lumbar disc herniation and persistent lumbar radiculopathy (Cohen and Griffith 2006). Initial data are encouraging.

Additionally, anti-IL-1β therapy is available with the drug anakinra (Kineret, Amben), which is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret blocks the biologic activity of IL-1β by competitively inhibiting IL-1β binding to the interleukin-1 type 1 receptor (IL-1R1). It is indicated for the reduction in signs and symptoms and slowing the progression of structural damage in active rheumatoid arthritis in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs. Kineret should not be used with TNF-α blocking agents. It is given subcutaneously in a dose of 100 mg on a daily basis.

Before the commercial development of monoclonal antibodies to TNF-α or soluble receptors, we tested the ability of thalidomide to reduce the painful and pathological consequences of CCI (Sommer and Schafers 1998). Typically, CCI produces a thermal hyperalgesia that peaks within the first week of injury and Wallerian degeneration and then slowly resolves during the phase of nerve regeneration. Thalidomide reduces the production of TNF-α by activated macrophages and significantly reduces the degree of thermal hyperalgesia during the peak of macrophage influx. When treatment was stopped, hyperalgesia increased.

Gene transfer therapy approaches with subcutaneous inoculation of soluble TNFR1-expressing herpes simplex virus vector inducing a local release of soluble TNFR1 to the DRG successfully decreased pain-related behavior after SNL by reducing membrane-bound TNF-α and concomitant reductions in IL-1β and phosphorylated p38 (Hao et al. 2007). Recently, an alternative strategy using active anti-TNF-α vaccination successfully reduced TNF-α-driven chronic and acute inflammation in mice (Le Buanec et al. 2006).

8.7.1. Anti-Inflammatory Cytokines

Upregulation of TNF-α also leads to compensatory increases in anti-inflammatory cytokines, such as IL-4 and IL-10, that down-regulate TNF-α production. We injected IL-10 directly into rat sciatic nerve following CCI to determine if this form of anti-TNF-α therapy reduced CCI hyperalgesia (Wagner et al. 1998). Hyperalgesia was significantly diminished throughout the experimental period. Thus, exogenous IL-10 therapy could be a means through which the detrimental effects of TNF-α can be regulated, a strategy now being explored in clinical trials for the management of sepsis and congestive heart failure (Kumar et al. 2005). More recently, intrathecal IL-10 gene delivery has been shown to produce a prolonged reversal of neuropathic pain (Milligan et al. 2006a, b). Anti-inflammatory cytokines may play a crucial role because of tight interactions with endogenous analgesia, for instance the opioidergic system (Kraus et al. 2001). The anti-inflammatory cytokine IL-4 also has analgesic effects in animal models of neuropathic pain (Hao et al. 2006; Vale et al. 2003).

In summary, cytokines are potent modulators of pain cascades through local reorganization in damaged tissue and nerve, activating acute pain cascades through direct neuronal excitability; intracellular MAPK; and other signaling cascades in local glial, endothelial, and mast cells, resulting in macrophage recruitment, sustained activation of local glia, and localized neuroinflammation. Through axonal transport and sustained neuronal excitability, cytokines can activate central glia in segmental spinal cord and cephalad pathways, promoting central neuroinflammation and persistent pain. Anti-nociceptive strategies include inhibition of proinflammatory cytokines and use of anti-inflammatory cytokines.

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