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date: 26 May 2019

Neurotrophins, Cytokines, and Pain

Abstract and Keywords

The neurotrophin and cytokine families of proteins regulate neuronal functions that affect survival, growth, and differentiation. Because of their extensive expression throughout the nervous system, some neurotrophins and cytokines are widely accepted to modulate synaptic plasticity and nociceptive processing. Among the neurotrophin family are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), which all bind to the tyrosine receptor kinases. The potential for BDNF as a therapeutic target is supported by a large body of evidence demonstrating its role in driving plastic changes in nociceptive pathways to initiate and maintain chronic pain. On the other hand, NGF has already proved fruitful as an analgesic target, with efficacy shown for NGF-neutralizing antibodies for pain relief in rheumatic diseases. The cytokine family includes the interleukins, tumor necrosis factors (TNFs), chemokines, interferons (IFNs), and transforming growth factor ß (TGF-ß) family. These bind, often promiscuously, to the heterogeneous group of cytokine receptors, and this cytokine signaling is essential for normal responses of the innate and adaptive immune systems. In pathophysiological states, chronic inflammation enhances the expression of pro-inflammatory cytokines, and many studies support a modulatory role of cytokines in nociceptive processes. At the forefront of anticytokine therapy for analgesia are TNF and IL6 monoclonal antibodies, which are licensed treatments for pain relief in rheumatoid arthritis. This chapter reviews the pro- and antinociceptive roles of key members of the neurotrophin and cytokine families in the context of chronic pain mechanisms and therapeutic approaches.

Keywords: neurotrophin, cytokine, chemokine, inflammation, plasticity, tanezumab, tocilizumab, etanercept

Background

Neurotrophins and cytokines are important regulators of the pain system. These families of proteins regulate neuronal functions affecting survival, growth, and differentiation, as well as influence cell fate choices and regulating neurite morphology. Neurotrophins are also able to regulate cell death and survival in development and pathophysiological states. Both neurotrophins and cytokines, and their receptors, are expressed in areas of the nervous system that are susceptible to plastic changes, and it is now widely accepted that some members of these protein families can modulate synaptic plasticity.

Neurotrophins are synthesized as high molecular weight precursors (proneurotrophins) that contain a prodomain linked to the N-termini of the mature protein. Endoproteolytic cleavage separates these precursors to be targeted for constitutive or for regulated secretion of the mature protein. For example, within hippocampal neurons, the endoprotease furin cleaves pro–nerve growth factor (pro-NGF) for constitutive secretion of NGF, whereas pro–brain-derived neurotrophic factor (pro-BDNF) is packaged in dense core vesicles to be cleaved by the endoprotease proprotein convertase 1(PC1) for mature BDNF to be sorted for the regulated secretory pathway, where it can be released in an activity-dependent manner. Mature neurotrophins exist as noncovalently linked homodimers whose monomers are between 13.5 and 13.9 kDa in size. The x-ray crystal structures of the mature neurotrophins reveal similarity in their conformations, with each homodimer containing three disulfide bridges. They are therefore a designated part of the cysteine knot superfamily (Dawbarn & Allen, 2003).

Cytokines are small proteins that are phylogenetically related to opioid peptides, ranging between 8 and 30 kDa, and function as signaling molecules at picomolar or nanomolar concentrations (Thomson & Lotze, 2003). Cytokines were originally identified as products of immune cells that mediate inflammatory responses of the innate immune system. It was later discovered that cytokines are produced in multiple cell types, including neurons, Schwann cells, and other glial cells, and that they also act on multiple cell types, including neurons and glia of the peripheral nervous system (PNS) and central nervous system (CNS). They thus provide a means of communication between the immune system and the nervous system, acting at hormonal concentrations through high-affinity receptors. Cytokines are grouped into families according to their binding to receptor complexes. Most cytokines use the intracellular Janus kinase–signal transducer and activator of transcription (JAK/STAT) pathway for signaling. Cell stressors like heat, ultraviolet light, or pathogens and inflammatory mediators acting via toll-like receptors (TLRs) activate mitogen-activated protein kinases (MAPKs), which in turn activate the synthesis of cytokines. Their action is controlled by a system of negative regulators (Bedoui, Neal, & Gasque, 2018; Yoshimura, Ito, Chikuma, Akanuma, & Nakatsukasa, 2018), including suppressor of cytokine signaling (SOCS) proteins and cytokine-inducible Src homology 2 (SH2)–containing (CIS) protein, a family of intracellular proteins. Any therapeutic manipulation in this system has to take into account that SOCS proteins are also involved in tumorigenesis (Yoshimura et al., 2018).

In this chapter, we review the role of key cytokines and neurotrophic factors that have been linked to nociceptive processing.

Neurotrophins and Pain

Some of the key members of the neutrophin family have been linked to nociceptive processes. This section discusses these members and their role in different chronic pain syndromes.

Key Features of Neurotrophins

Some of the key members of the neurotrophin family that have been linked to nociceptive processes include NGF, BDNF, and neurotrophin 3 (NT-3). All neurotrophins bind to the p75 pan-neurotrophin cell surface receptor with similar affinity, although NGF binds preferentially to TrkA (tropomyosin-related kinase A) receptors, BDNF and NT4/5 to TrkB receptors, and NT-3 to TrkC receptors and (to a lesser extent) TrkA receptors (Figure 1). The distribution of messenger RNAs (mRNAs) for different Trk receptors has been determined in rat dorsal root ganglia (DRG) neurons using in situ hybridization and retrograde labeling, displaying preferential expression of TrkA in visceral afferents and TrkC in muscle afferents, and coexpression of TrkB with either TrkA or TrkC in almost all neurons (McMahon, Armanini, Ling, & Phillips, 1994). Little overlap in TrkA and TrkC expression was reported in cutaneous afferents, indicating that NGF and NT-3 act on functionally distinct populations of adult sensory neurons (Wright & Snider, 1995). Here, we discuss in detail the role of different members of the neurotrophin family in the development of sensory neurons, in nociceptive signaling, and in chronic pain.

Neurotrophins, Cytokines, and PainClick to view larger

Figure 1. Neurotrophin receptors and the intracellular pathways activated downstream of their activation. All neurotrophins bind to the p75 pan neurotrophin cell surface receptor with similar low affinity, although NGF binds preferentially to TrkA (tropomyosin-related kinase A) receptors, BDNF and NT4/5 to TrkB receptors, and NT-3 to TrkC and TrkA receptors. Downstream signaling following activation of neurotrophic receptors determines cell survival and differentiation, as well as changes in synaptic plasticity, which can affect nociceptive processing in sensory neurons. BDNF, brain-derived neurotrophic factor; KCC, K-Cl cotransporter; c-Jun N-terminal kinase; NFκB, nuclear factor kappa B; NGF, nerve growth factor; NT, neurotrophic; Trk, tropomyosine receptor kinase.

Brain-Derived Neurotrophic Factor

This section covers BDNF’s synthesis, expression, signaling, and role in chronic pain.

Synthesis and Expression

Brain-derived neurotrophic factor is a member of the neurotrophin superfamily long known to regulate the survival of subsets of peripheral and central neurons during development, cells in the DRG, trigeminal ganglia, and nodose ganglion (Ernfors, Lee, & Jaenisch, 1994). The BDNF gene consists of eight noncoding 5′ exons (I–VIII) and one 3′ exon (IX) encoding BDNF protein. Exons I, VII, VIII, and IX contain ATG (adenine-thymine-guanine) sequences that are transcription initiation sites and two polyadenylation (polyA) sites in exon IX that serve as transcription termination sites, yielding two mRNAs with either short or long 3′ untranslated regions (UTRs) (Lau et al., 2010). The BDNF gene structure and transcription mechanisms are complex, which results in multiple BDNF mRNA variants, yet produces identical pre–pro-BDNF proteins. The different BDNF mRNAs have distinct distribution within neurons, suggesting specific transport systems or local dendric translation of BDNF; the shorter 3′ UTR variant is restricted to the cell body, while the longer 3′ UTR variant is present in dendrites (O’Neill, Donohue, Omelchenko, & Firestein, 2018).

The prodomain of BDNF is essential for correct folding and targeting the protein to secretory pathways. It also binds to p75 receptors and sortilin to exert mainly opposing biological effects of mature BDNF in the CNS, that is, promoting neuronal apoptosis and axon pruning and negatively regulating hippocampal dendritic spine density (Marler, Poopalasundaram, Broom, Wentzel, & Drescher, 2010). Mature BDNF is stored and released from both axons and dendrites in response to excitatory synaptic activity, such that it is released in an activity-dependent manner to modulate synaptic plasticity (Kuczewski, Porcher, & Gaiarsa, 2010). BDNF can be stored in either secretory vesicles or endoplasmic reticulum–derived tubular structures in hippocampal neurons (Gartner, Shostak, Hackel, Ethell, & Thoenen, 2000); it is also stored in cytoplasmic dense core vesicles in the terminals of primary sensory neurons in the dorsal horn (Luo, Rush, & Zhou, 2001).

Expression of BDNF in the adult is largely restricted to small- and medium-size sensory neurons that also express calcitonin gene–related peptide (CGRP) and TRKA (Michael et al., 1997), whereas its high-affinity receptor NTRK2, or TRKB, is expressed in intermediate- to large-size neurons that give rise to myelinated axons (McMahon et al., 1994). In BDNF knockout (KO) mice, slowly adapting mechanoreceptors show a deficit in mechanical sensitivity, indicating a possible role for BDNF in regulating fine tactile discrimination (Carroll, Lewin, Koltzenburg, Toyka, & Thoenen, 1998), although deletion of BDNF in sensory neurons does not alter acute sensory processing of innocuous and noxious mechanical and thermal stimuli (Sikandar et al., 2018).

BDNF Signaling

Mature BDNF binds with strong affinity to TrkB receptors, which are widely expressed throughout the brain (including the neocortex, hippocampus, cerebellum, and brainstem) and spinal cord (Yan et al., 1997). BDNF expressed in DRG is released in an activity-dependent fashion in the spinal dorsal horn, activating pre-synaptic or postsynaptic TrkB receptors on primary afferent endings or second-order dorsal horn neurons, respectively, leading to excitatory neurotransmission (Lever et al., 2001). BDNF also exerts a bidirectional effect on GABA (γ-aminobutyric acid)–mediated (GABAergic) transmission via both pre- and postsynaptic mechanisms. In immature neurons where GABAA receptors mediate excitatory responses, BDNF potentiates GABAergic transmission facilitate activity-dependent synaptic maturation, and in mature neurons where GABAA receptors typically mediate inhibitory responses, BDNF can inhibit GABAergic transmission (Mizoguchi, Ishibashi, & Nabekura, 2003). Inhibitory effects of BDNF on GABAA receptor–mediated transmission have been reported throughout the nervous system, including the hippocampus, ventral tegmental area, and dorsal horn (J. T. Chen et al., 2014; Vargas-Perez et al., 2009).

Binding of BDNF triggers TrkB dimerization, followed by autophosphorylation of tyrosine residues in the receptor, resulting in the recruitment of adaptor proteins and transduction molecules that activate downstream phosphorylation cascades that can promote protein synthesis, axonal growth, dendritic maturation, use-dependent synaptic plasticity, and neuroprotection. Activation of Ras proteins initiates the mitogen-activated protein kinase (MEK)/ERK pathway. Phosphatidylinositol 3-kinase (PI3K) activates Akt (protein kinase B). Last, phospholipase Cγ (PLCγ) leads to the production of diacylglycerol and activation of protein kinase C (PKC) and inositol triphosphate (IP3) to encourage Ca2+ release from intracellular stores. Targets from these three cascades include cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), actin-binding proteins, and mammalian (mechanistic) target of rapamycin (mTOR). Several targets from these cascades, including transcription factors such as CREB, actin-binding proteins, and transcriptional regulators such as mTOR alter protein synthesis and regulate synaptic plasticity.

In contrast, pro-BDNF primarily binds to the low-affinity nonselective neurotrophin receptor p75NTR, which is predominantly expressed in basal forebrain cholinergic neurons in the adult CNS and triggers proapoptotic signaling (Teng et al., 2005).

BDNF in Chronic Pain

Brain-derived neurotrophic factor is a well-known mediator of pain plasticity that can cause the induction and maintenance of long-term potentiation (LTP) in the brain and spinal cord. Bdnf mRNA and protein expression are increased in DRG following exposure to NGF or inflammatory stimuli (Kerr et al., 1999; Mannion et al., 1999), and primary afferent-derived BDNF is required for the generation of hyperalgesic priming (Melemedjian et al., 2013; Sikandar et al., 2018). Importantly, BDNF signals contribute to the activity-dependent increase in the number and volume of dendritic spines at glutamatergic synapses, which is critical for maintenance of LTP at spinal and supraspinal levels, including the hippocampus and amygdala (Patterson et al., 1996). The short-term effects of BDNF-induced LTP involves phosphorylation cascades that modulate N-methyl-d-aspartate (NMDA) receptor function, membrane insertion of NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits and the function of voltage-gated sodium and potassium channels and transient receptor potential canonical subfamily C3 (TRPC3) channels (Levine, Crozier, Black, & Plummer, 1998; Tucker & Fadool, 2002). In contrast to mature BDNF, which promotes LTP via TrkB signaling pathways, pro-BDNF acts via the p75NTR to reduce dendritic complexity and spine density in hippocampal neurons and promotes NMDA receptor–mediated long-term depression (Woo et al., 2005).

Also, BDNF was linked to translational control of gene expression in the nervous system (Melemedjian et al., 2013; Woo et al., 2005). Protein translation involves phosphorylation of eukaryote initiation factor eIF4E binding protein 1 by the mTOR complex, allowing dissociation from eIF4E and ribosomal S6 protein and initiation of the translation of mRNAs (Showkat, Beigh, Bhat, Batool, & Andrabi, 2014). Phosphorylation of eIF4E is essential for Bdnf mRNA translation in the DRG and nociceptor plasticity that leads to hyperalgesic priming (Moy, Khoutorsky, Asiedu, Dussor, & Price, 2018). In mice lacking eIF4E phosphorylation, nociceptive stimuli fail to increase BDNF protein levels in the DRGs of these mice despite robust upregulation of Bdnf mRNA levels, but intrathecal injection of BDNF can restore their response to hyperalgesic priming (Moy et al., 2018). BDNF also promotes translation of synaptic proteins by downregulating expression of the gene encoding fragile X mental retardation protein 1 (FMRP1) and triggers inhibitory dephosphorylation of FMRP1 to promote activity-dependent translation of FMRP1-inhibited mRNAs, including proteins involved in synaptic plasticity (Schratt, Nigh, Chen, Hu, & Greenberg, 2004). These studies support the role of BDNF in the initiation and maintenance of plasticity in the nervous system, which is a key mechanism for the development of chronic pain (Reichling & Levine, 2009).

It is well established that exogenous BDNF can facilitate spinal reflexes and increase primary afferent evoked postsynaptic currents (Kerr et al., 1999). Exogenous BDNF applied to an in vitro spinal cord preparation enhanced C-fiber–evoked reflexes recorded in the ventral root, and this can be attenuated with sequestration of endogenous BDNF using TrkB–immunoglobulin G (IgG) (in animals pretreated with NGF to increase BDNF expression in the DRG) (Kerr et al., 1999). These studies support a role for BDNF as a modulator of central sensitization in pathological pain states. Indeed, it has been reported that BDNF derived from microglia drove pain behavior in a model of sciatic nerve cuffing (Coull et al., 2005), and BDNF derived from myelinated afferents was dramatically increased following spinal nerve transection (Obata et al., 2006). An important consideration here is the contribution of distinct neuronal subsets across different rodent models of neuropathy to nociceptive signaling (Minett et al., 2012) and differences in levels of BDNF expression in DRG following rhizotomy and transection neuropathic pain models (Obata et al., 2006).

The BDNF derived from sensory neurons also plays a critical role in the transition from acute to chronic pain, as deletion of BDNF from Advillin-expressing neurons abolished second-phase, formalin-induced nociceptive behavior, neuropathic pain behavior, and responses to hyperalgesic priming induced using prior provision of intraplantar carrageenan (Sikandar et al., 2018). Importantly, primary afferent–derived BDNF does not significantly contribute to acute nociceptive behavior or basal excitability of wide dynamic range neurons in the deep dorsal horn (Sikandar et al., 2018). Multiple reports support this pronociceptive role of BDNF in pain chronification; spinal BDNF mediates prolonged prostaglandin E2 (PGE2) sensitivity in rodents primed with interleukin 6 (IL-6), and sequestering BDNF in the cisterna magna can prevent IL-6–mediated hyperalgesic priming in a model of migraine (Burgos-Vega, Quigley, Avona, Price, & Dussor, 2016; Melemedjian et al., 2013). These studies support the role of BDNF in the development and maintenance of chronic pain through translational control of synaptic proteins and synaptic plasticity, as well as presynaptic inhibitory control of nociceptive signaling in the dorsal horn (J. T. Chen et al., 2014; Moy et al., 2018).

Nerve Growth Factor

Here we provide an overview of NGF during development and its role in nociceptive signaling and chronic pain in the adult somatosensory system

NGF in Development

Nerve growth factor is a 13-kDa polypeptide first discovered in the 1950s as a trophic agent for sympathetic and sensory neurons (Levi-Montalcini & Cohen, 1956). Its critical role in neuronal development led to the development of the “neurotrophic factor hypothesis,” where synthesis and release of neurotrophic factors can promote growth, differentiation, and survival of neurons in a dose-dependent manner. A subsequent wealth of studies on NGF demonstrated a more complex nature for the role of neurotrophic factors in neuronal survival and development than a basic competition among developing neurons for a limited supply of a neurotrophic factor provided by the target tissue. Instead, regulatory and temporal patterns for neurotrophin expression can influence survival in different neuronal populations of the mammalian nervous system.

NGF signaling is key for the development of the sensory and sympathetic nervous systems and in maintenance of the cholinergic neurons in the basal forebrain. All nociceptive sensory neurons require NGF for survival during early development, and postnatal treatment in rats with anti-NGF from day 0 to 5 weeks results in depletion of high-threshold mechanoreceptors and an increase in low-threshold mechanoreceptive D-hair afferents (Ritter, Lewin, Kremer, & Mendell, 1991). This dependence is lost 1–2 weeks postnatally in the rodent, where nearly half of all sensory neurons switch from expression of TrkA to receptors for glial cell–derived neurotrophic factor. Sympathetic postganglionic neurons also express TrkA from early in development and throughout adulthood (Aloe, Mugnaini, & Levi-Montalcini, 1975).

NGF Signaling

Nerve growth factor binds with high affinity to TrkA to cause homodimerization, autophosphorylation, and subsequent endocytosis of the ligand–receptor complex, leading to retrograde transport in signaling endosomes (Ginty & Segal, 2002). Synergistic action between TrkA and p75NTR has also been demonstrated to enhance growth (Bibel, Hoppe, & Barde, 1999). The complexity of NGF signaling is underscored by the ability of p75NTR to form heterodimers with other auxiliary receptors (including sortilin) (Skeldal et al., 2012), the ability of extracellular pro-NGF to bind to p75NTR and the transactivation of TrkA by other G protein-coupled receptors (Rajagopal, Chen, Lee, & Chao, 2004).

A majority of studies suggested that NGF is minimally expressed under normal conditions in the adult despite the wide expression of TrkA and p75NTR in one half of adult nociceptors, DRG satellite cells, and Schwann cells (Thakur et al., 2014; Tomita et al., 2007). Under normal conditions, NGF transcripts are absent in mouse bone-derived and human blood-derived mast cells as well as human keratinocytes (Cavazza et al., 2016). NGF expression is also absent in microglia, mouse DRG, and human trigeminal and DRG (Denk, Crow, Didangelos, Lopes, & McMahon, 2016; Flegel et al., 2015; Usoskin et al., 2015). However, in pathological states, NGF expression and protein levels are increased, particularly with associated inflammation, and this expression of NGF in the adult has been linked to mast cells, macrophages, and keratinocytes (Barouch, Kazimirsky, Appel, & Brodie, 2001; Leon et al., 1994; Shi, Wang, Clark, & Kingery, 2013). In humans, increased NGF levels have been reported in cases where pain is a presenting feature, and endogenous levels of NGF are increased in conditions such as interstitial cystitis, arthritis, and pancreatitis (Friess et al., 1999; Halliday, Zettler, Rush, Scicchitano, & McNeil, 1998; Lowe et al., 1997).

Nerve growth factor application to primary sensory neurons in culture results in activation of TrkA and sensitization of these TrkA-positive neurons to noxious heat, mechanical stimulation, and chemical stimulation with capsaicin (Winter, Forbes, Sternberg, & Lindsay, 1988). TrkA activation is thought to trigger downstream cascades involving PI3K and MAPK with activation of PKCγ and phosphatidylinositol 4,5-bisphosphate (PIP2) (Cao, Cordero-Morales, Liu, Qin, & Julius, 2013). These intracellular cascades are also linked to increased phosphorylation and subsequent trafficking of transient receptor potential cation channel subfamily V member 1 (TRPV1), and in the naked mole rat, reduced TrkA function results in decreased ability to trigger signal transduction pathways that sensitize TRPV1 following exposure to NGF (Omerbasic et al., 2016).

NGF in Chronic Pain

Several lines of evidence in human studies suggest that NGF is a mediator of nociceptive signaling in mature mammals. First, NGF injected into healthy human skin will rapidly produce localized pain and hypersensitivity within minutes, indicative of a sensitizing effect on nociceptors at the injection site (Petty et al., 1994). Second, rare genetic polymorphisms in the NTRK1 and NGF genes have been linked to altered pain perception. Autosomal recessive mutations across the 17 exons of NTRK1 lead to congenital insensitivity to pain with anhydrosis, also referred to as hereditary and autonomic neuropathy type IV (Indo et al., 1996). Ultrastructure analysis of peripheral nerves in these patients have shown substantial loss of unmyelinated fibers, mild loss of small-diameter myelinated primary afferents, and absent innervation of sweat glands (Langer, Goebel, & Veit, 1981). The major clinical characteristics are insensitivity to noxious stimuli (leading to self-mutilating behavior), cognitive dysfunction, and anhydrosis. The insensitivity to pain is associated with attenuated development of small nociceptive neurons in the DRG, and the abnormal innervation of eccrine sweat glands by cholinergic sympathetic fibers leads to anhydrosis and hyperthermia. NTRK1-deficient mice lack almost all small neurons (nociceptors) in the DRG, demonstrate substantial neuronal cell loss in the sympathetic ganglia, and have decreased cholinergic neurons in the basal forebrain (Smeyne et al., 1994).

A homozygous missense mutation in the NGF beta gene leads to a disorder termed hereditary sensory and autonomic neuropathy type V (Larsson, Kuma, Norberg, Minde, & Holmberg, 2009). This results in a form of pro-NGF that is resistant to cleavage, likely leading to reduced levels of mature NGF throughout development. Patients also display similar developmental consequences to loss of NGF and reduced survival of peripheral nociceptors, although the differences in phenotypic contribution of mature NGF compared to overexpression of pro-NGF is still unclear.

Direct administration or overexpression of NGF in rodent studies has also been shown to produce sensitization of sensory neurons. In early studies in rats, NGF was administered over a 5-week period from birth, leading to a substantial decrease in withdrawal latency from a noxious thermal stimulus (Lewin & Mendell, 1994). To distinguish between developmental or physiological mechanisms, it was also shown that a single intraperitoneal administration of NGF in adult rats produced thermal hyperalgesia for several days (Lewin, Ritter, & Mendell, 1993). Pig studies showed a role for low-dose subcutaneous injections of NGF subcutaneously to modulate electrophysiological properties of nociceptors, with a latency of several weeks (Jonas, Klusch, Schmelz, Petersen, & Carr, 2015). These findings suggest transcriptional mechanisms for NGF modulation of neuronal excitability, and NGF has been shown to promote gene expression for axonal growth (Zhou, Zhou, Dedhar, Wu, & Snider, 2004).

Neurotrophin-3

In this section we discuss the role of neurotrophin-3 (NT-3) in development and in chronic pain.

NT-3 in Development

In most cases, neurotrophins can modulate cell number by regulating programmed cell death. The primary effect of neurotrophin action tends to be on postmitotic neurons, although during early embyrogenesis NT-3 supports survival of neuronal precursors and can prevent terminal differentiation of precursor cells (Farinas, Yoshida, Backus, & Reichardt, 1996). NT-3 KO mice therefore exhibit waves of enhanced cell death during the period of neurogenesis (prior to E12.5) and during the normal period of programmed cell death (after E13.5) (Liebl, Tessarollo, Palko, & Parada, 1997). NT-3 expression in the nervous system, along with NGF, can influence nociceptor development. NT-3 gene deletion leads to similar proportions of sensory and sympathetic neuron depletion compared to NGF deletion, including spinal proprioceptive afferents expressing parvalbumin and carbonic anhydrase (Ernfors, Lee, Kucera, & Jaenisch, 1994). And, similar to NGF, overexpression of NT-3 in the skin leads to an increase in myelinated and unmyelinated sensory nerve fibers (Stucky et al., 1999).

NT-3 KO mice demonstrate the necessity of NT-3 expression for nociceptor survival, as these mice exhibit altered whisker pad innervation with loss of all un- and thinly myelinated neurons innervating the epidermis and upper dermis, an effect thought to be mediated via TrkA dependency as TrkC deletion does not recapitulate this phenotype (Rice et al., 1998). NT-3 activation of TrkA and TrkB sustains survival of multiple subsets of sensory neurons and promotes the formation of sensory endings; it therefore plays a role in regulating sensory dermatomal boundaries in the adult nervous system (Ritter, Woodbury, Davis, Albers, & Koerber, 2001). These pathways also stimulate epidermal keratinocyte proliferation and hair follicle development (Botchkarev, Botchkareva, Peters, & Paus, 2004). In the adult, cutaneous TrkC-expressing mechanoreceptors are NT-3 sensitive, and exposure to a localized source of NT-3 can induce attractive growth cone via regulation of actin and adhesion receptors (Marsick, San Miguel-Ruiz, & Letourneau, 2012).

NT-3 in Chronic Pain

Although NT-3 does not alter behavioral phenotypes or neuronal excitability in skin nerve preparations in normal states, it does show pro- and antinociceptive effects in models of spinal cord injury and neuropathy. In the developing nervous system, NT-3 mediates sensory nerve sprouting following skin injury (Beggs et al., 2012). In the adult rodent, axotomy and NT-3 exposure can downregulate potassium channels Kv 1.2, 1.4, and 4.2 mRNA expression in DRG neurons, suggesting that NT-3 can contribute to the injury-related synaptic plasticity of primary afferents (Park et al., 2003). On the other hand, NT-3 has been shown to have regenerative capacity in a model of spinal cord injury, promoting growth of lesioned dorsal column axons and fiber sprouting at the lesion site (Bradbury et al., 1999).

Indeed, in normal adult rats, intrathecal administration of exogenous NT-3 does cause an expansion of the area of termination of Aβ-fibers in the spinal cord and allodynia, diminishing the potential clinical use for NT-3 for neuronal regeneration after injury (White, 2000).

Other studies have shown an antinociceptive role for NT-3 in models of neuropathic pain; in rats with streptozotocin-induced diabetes, intramuscular administration of recombinant adenovirus encoding NT-3 prevented the slowing of motor and nerve conduction velocities (Pradat et al., 2001). However, following spinal nerve transection and partial sciatic nerve ligation, intrathecal administration of NT-3 antisense oligonucleotides attenuated allodynia and sprouting of large myelinated fibers (White, 2000). These findings are consistent with a role for NT-3 in modulating nociceptive signaling in chronic pain via changes in synaptic plasticity and nerve growth.

Neurotrophins and Analgesic Therapies

In this section we address NGF as a therapeutic target, and neurotrophic factors in osteoarthritis (OA), cancer pain, low back pain, and safety.

NGF as a Therapeutic Target

Nerve growth factor signaling is linked to profound and long-lasting sensitizing effects on the nociceptive system in both rodents and humans. Augmented expression of NGF mRNA and protein expression have been reported in several human pain disorders (largely linked to inflammation), including OA (Iannone et al., 2002); rheumatoid arthritis (RA) and spondyloarthritis (Aloe, Tuveri, Carcassi, & Levi-Montalcini, 1992; Barthel et al., 2009); chronic pancreatitis (Friess et al., 1999); interstitial cystitis (W. Chen et al., 2016); and inflammatory bowel disease (di Mola et al., 2000) and in a model of ultraviolet B skin burn (Dawes et al., 2011). These reports indicated NGF as a potential therapeutic target for pain relief, particularly in pathologies with associated inflammation.

In rodent studies, thermal and mechanical hypersensitivity evoked by paw inflammation following intraplantar complete Freund’s adjuvant or carrageenan can be blocked using antibodies to NGF delivered systemically or a sequestering TrkA–IgG fusion molecule delivered locally to the hind paw (McMahon, Bennett, Priestley, & Shelton, 1995). Importantly, anti-NGF therapy was reported to produce analgesia without affecting edema, suggesting that targeting NGF will modulate nociceptor sensitization without influencing the inflammatory response. Anti-NGF therapy has also been reported to have analgesic efficacy in preclinical models of human pain disorders, including cancer-induced bone pain, a tibia fracture model of complex regional pain syndrome and a plantar incision postsurgical pain model (Sabsovich et al., 2008; Sevcik et al., 2005; Zahn, Subieta, Park, & Brennan, 2004).

Osteoarthritis

Several positive clinical trials for the treatment of OA supported the use of anti-NGF for analgesia. Drugs that have been developed to relieve OA pain include free NGF–capturing agents and antagonists of TrkA. Tanezumab, or the NGF-capturing agent RN624, is a highly selective humanized Ig G2 monoclonal antibody that binds to and neutralizes NGF bioactivity (Schnitzer & Marks, 2015). Tanezumab was first shown to have significant therapeutic potential in a Phase II randomized controlled trial (RCT) of knee OA, with significant reductions ranging from 45% to 62%, including knee pain, stiffness, and limitations of physical function (Lane et al., 2010). A systematic review covering 13 Phase II and Phase III RCTs using anti-NGF monoclonals (including tanezumab, fasinumab, fulranumab, and PG110) showed efficacy in reducing pain and improving function compared to placebo, nonsteroidal anti-inflammatory drugs (NSAIDs), and opiate treatment (Schnitzer & Marks, 2015). Tanezumab also showed the greatest efficacy compared to other monoclonal treatments.

A key consideration in targeting TrkA rather than NGF is the homology between different Trk receptors. The more recent development of surface plasmon resonance technology has led to evaluation of the inhibitory potentials of ALE-0540, PD90780, Ro 08-2750, and PQC083, compounds that inhibit NGF binding, rather than TrkA and p75NTR receptors (Sheffield, Kennedy, Scott, & Ross, 2016). PD90780 is reported to be most effective in inhibition of NGF–TrkA and NGF–p75NTR interactions and provides promising therapeutic potential for clinical trials.

Cancer Pain

Rodent studies have shown that TrkA sensory nerves innervate the developing femur to facilitate formation of primary and secondary ossification centers, leading to abundant sensory innervation at the periosteal and endosteal surfaces in the mature mammalian skeleton (Tomlinson et al., 2016). Sprouting of TrkA-expressing nerve fibers has also been observed in skeletal pain states following skeletal injury or disease (Tomlinson et al., 2017). These findings support the notion that blocking NGF or TrkA signaling in skeletal pain could cause pathological remodeling of sensory and sympathetic nerve fibers that can be the primary source of hypersensitivity in chronic skeletal pain states. Pain is a primary feature in cancer that metastasizes to the bone, and analgesic efficacy of the NGF neutralizing antibody tanezumab has been tested in patients with metastatic bone cancer. One placebo-controlled parent study with a single intravenous injection of 10 mg tanezumab or placebo was followed by a 40-week uncontrolled, open-label extension period with intravenous infusions of 10 mg tanezumab at 8-week intervals (Sopata et al., 2015). Outcomes of this study showed no significant change in daily average pain scores, but a post hoc analysis suggested greater efficacy of tanezumab in patients with lower baseline opioid use or higher baseline pain. In the 40-week extension, patients reported a significant decrease in pain scores compared to the baselines in the parent and extension studies. Tanezumab may therefore provide additional sustained analgesia in patients with metastatic bone pain with daily opioid consumption.

Low Back Pain

A proof-of-concept study in 2011 showed the analgesic efficacy of tanezumab in adult patients with chronic nonradicular low back pain (Kivitz et al., 2013). At 6 weeks, patients in the tanezumab treatment arm (200 µg/kg iv twice daily) reported significantly greater reductions in pain intensity and corresponding improvements in physical function compared to naproxen- and placebo-treated groups. Arthralgia, pain in extremities, headache, and paresthesia were the most commonly reported adverse events by tanezumab-treated patients. A successive open-label extension study was carried out to further evaluate the long-term safety and efficacy of tanezumab using patients from the aforementioned 16-week parent study, and all patients reported improvements in pain from baseline in a dose-dependent manner (Kivitz et al., 2013).

Additional Phase II studies in patients with chronic low back pain have been undertaken using the NGF-neutralizing antibodies fulranumab and fasinumab, but these studies failed to show significant analgesic efficacies. Subcutaneous injections of fulranumab in doses ranging from 1 to 10 mg at 4-week intervals failed to achieve a significant reduction in average daily pain by Week 12 (Sanga, Polverejan, Wang, Kelly, & Thipphawong, 2016). Patients diagnosed with radicular pain received fasinumab as a single subcutaneous injection at doses of 0.1 mg/kg (n = 54) and 0.3 mg/kg, and again demonstrated no benefit for improvement of average daily back or leg pain by 4 weeks compared to placebo (Tiseo, Ren, & Mellis, 2014).

Safety

In 2010, all clinical trials for anti-NGF antibodies were put on hold by the Food and Drug Administration (FDA) due to reports of rapidly progressive OA and osteonecrosis, leading to joint replacement, most commonly of the knee and hip. Reported cases occurred in subjects receiving tanezumab, tanezumab with NSAIDs, or fulranumab and involved extensive bone damage and joint destruction. These cases were characterized by distinct pathological features, including femoral head flattening and medial femoral condyle involvement with subchondral fractures, as well as associated edema, joint effusions, and pain (Hochberg, 2015). In 2012, the FDA commissioned an independent advisory committee, which concluded that the joint failures were likely related to the anti-NGF treatment and represented a unique clinical form of rapidly progressive OA. Although the precise etiology of the joint destruction is still not clear, plausible mechanisms may relate to the susceptibility of some patients with atrophic and neuropathic forms of OA or due to the combination of NSAIDs and anti-NGF in impeding bone healing (Harder & An, 2003). The hold was lifted in March 2015 conditional on monitoring autonomic function and careful radiographic screening.

The development of sympathetic neurons is NGF dependent (Aloe et al., 1975), and tanezumab exposure in nonhuman primates has been associated with stereological changes in sympathetic ganglia, including smaller ganglion volume and smaller average neuronal size (Belanger et al., 2017). However, these effects were reported to be completely reversed on tanezumab withdrawal, and tanezumab had no adverse effects on sympathetic control of cardiovascular function (Belanger et al., 2017).

Cytokines and Pain

The relationship between cytokines and pain is explored in the following section of this chapter. We provide an overview of cytokine signaling in nociception, the interleukin (IL) and tumor necrosis factor (TNF) families, the chemokine superfamily, the role of cytokines in chronic pain, and clinical trials with analgesic drugs that modulate the cytokine system.

Key Features of Cytokine Signaling

The cytokine family includes ILs (consecutively numbered from IL-1 to, at present, IL-38), TNF, the chemokines (CXC, CC, and other subfamilies, consecutively numbered), the interferons (IFNs), and the transforming growth factor beta (TGF-ß) family. The activation or dysregulation of cytokines has been shown in a variety of disease states, such as sepsis, RA, Crohn disease, multiple sclerosis, neurodegenerative diseases, skin diseases, malignancies, pain, and many more. In more general terms, in health the cytokine response of the innate immune system in humans is balanced and self-limiting and thus apt to prevent tissue damage in case of contact with infectious agents. In disease, and particularly with aging, chronic inflammation with elevated expression of pro-inflammatory cytokines may turn into a detrimental factor, inducing and accelerating chronic inflammatory, neurodegenerative, and other diseases. This is generally attributed to failure of the endogenous anti-inflammatory system. As elegantly shown in a study with young mice, young individuals may be primed for later developing neuropathic pain when the endogenous anti-inflammatory system fails in age or with concomitant disease (McKelvey, Berta, Old, Ji, & Fitzgerald, 2015).

Cytokine receptors are a heterogeneous group. Some belong to the Ig superfamily, such as the IL-1 receptors. Others are G protein–coupled receptors with a seven-transmembrane helix protein, like the receptors for IL-8 and several chemokines. The receptors of the cytokine Type I and Type II receptor family with the prototype IL-6 are part of a homo- or heterodimer with glycoprotein kDa 130 (gp130). The receptors of the TNF family have a cysteine-rich extracellular binding domain and form trimeric complexes when activated, which then initiate downstream signaling. They can be enzymatically cut from the membrane and then act as soluble receptors (Ebersberger, 2018).

Cytokine Signaling and Nociception

A connection between cytokines and pain was first observed in the context of the “sickness response,” the response of organisms to infection, associated with fever, fatigue, loss of appetite, and hyperalgesia (Watkins & Maier, 2005). Hyperalgesia is regarded as part of the cytokine-mediated adaptive changes during illness or injury, potentially promoting recuperation by decreasing energy use. In chronic inflammatory diseases like RA, TNF and IL-1ß are important pathogenic molecules, and specific inhibitors can reduce both disease progression and pain (Arend & Dayer, 1990). In early studies, cytokines were mostly regarded as mediators that induced the release of further algesic substances like prostaglandins or bradykinin, the known inducers of pain, as well as neuropeptides like Substance P and CGRP. While this may be relevant in inflammatory pain, additional mechanisms may prevail in neuropathic pain.

A number of cytokines and chemokines have been studied in the context of pain. Among the pro-inflammatory cytokines, IL-1, IL-2, IL-6, IL-8, and TNF are key cytokines associated with nociceptive signaling. Anti-inflammatory cytokines linked to pain include IL-4, IL-10, IL-13, and TGF-ß. In the group of chemokines and chemokine receptors, research has focused on fractalkine/CX3CL1 (chemokine ligand 1), SDF-1/CXCL12, monocyte chemoattractant protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1a (MIP-1a)/CCL3, Regulated on Activation, Normal T-Cell Expressed, and Secreted (RANTES)/CCL5, and their respective receptors, CX3CR1, CXCR4, CCR2, CCR1, and CCR5.

In many studies of pain mechanisms, correlative data show changes in cytokine expression in nervous tissue in various animal models of chronic pain. Lesioning a peripheral nerve results in rapid local increase of pro-inflammatory cytokines (Fregnan, Muratori, Simoes, Giacobini-Robecchi, & Raimondo, 2012). For example, minor damage like repetitive strain injury or skin incision and gentle manipulation of the sciatic nerve is sufficient to increase local levels of TNF (Al-Shatti, Barr, Safadi, Amin, & Barbe, 2005). Sciatic nerve transection (SNT) leads to local upregulation of TNF, IL-1α, and IL-1ß in mice. Nerve crush, which leads only to inconsistent pain behavior in animals, induces just moderate local cytokine changes. In models of painful nerve injury, like the chronic constriction injury (CCI) of the sciatic nerve, there is rapid and sustained upregulation of TNF, IL-1ß, and IL-6 in the damaged nerve itself and in the DRG within hours (Üçeyler, Tscharke, & Sommer, 2007). Gene expression of the anti-inflammatory cytokine IL-10 increases in the first postlesion hours after CCI (Üçeyler, Tscharke, et al., 2007), and a second delayed peak is observed after 45 days (Okamoto, Martin, Schmelzer, Mitsui, & Low, 2001), which may indicate a role in nerve regeneration and possibly in the remission of hyperalgesia.

Studies of cytokine regulation in pain-related brain areas in inflammation or after peripheral nerve lesion have produced variable results. Several studies showed an upregulation of central pro-inflammatory cytokines. In rats with CCI, TNF bioactivity was increased in the hippocampus and the locus coeruleus. SNT lead to increased TNF, IL-1ß, and IL-6 protein levels when measured in the entire brain (W. R. Xie et al., 2006) or in the anterior half of the brain contralateral to the lesion. Treatment with steroids or with pentoxifylline, in turn, reduced the pro-inflammatory cytokine levels, increased the cerebral expression of IL-10, and led to pain relief. However, when single pain-related brain areas were investigated, no changes or even a reduction of pro-inflammatory cytokines were found. CCI, for instance, has no effect on IL-1ß gene expression in the brainstem and the frontal cortex in mice and even leads to a decrease of IL-1ß mRNA levels in the thalamus (Apkarian et al., 2006). Glutamate-dependent decrease of the gene expression of TNF, IL-1ß, and IL-4 in the first 6 hours after CCI in frontal cortex, hypothalamus, thalamus, and hippocampus in mice (Üçeyler, Tscharke, & Sommer, 2008). Some of the discrepancies in central cytokine regulation reported in the studies using animal models may be due to gender differences. For example, TLR4 is needed for inflammation- and nerve injury–related pain behavior in male but not female mice (Sorge et al., 2011), and the innate immune system may be more closely linked to pain in men than in women.

Key factors need to be taken into consideration when determining the pro- or antinociceptive role of cytokines in nociceptive processing. In contrast to circulating hormones, cytokines exert their effects over short distances onto nearby cells. Therefore, due to local cytokine effects at low concentrations (a few picograms to nanograms per milliliter), serum levels may not reliably reflect activity. Cytokines are “pleiotropic,” given their broad range of redundant, frequently overlapping functions. Further labeling refers to cytokines as “pro-inflammatory” (or Th1) or “anti-inflammatory” (or Th2), depending on their effects on immune cells, in particular on lymphocytes. However, certain cytokines may have pro- or anti-inflammatory actions, depending on the particular microenvironment, and can enhance activity in the pain pathways by direct and indirect ways (Table 1).

Table 1. Human Painful Disorders with a Presumed Role of Cytokines or Chemokines (Examples)

Disease

Cytokine, Chemokinea

Rheumatoid arthritis

TNF, IL-1ß, IL-6, IL-17A, CCL2 increased (serum and synovial fluid)

Craniomandibular dysfunction

IL-1ß, IL-6, TNF increased

Leprosy

TNF, IL-1ß increased

Painful peripheral neuropathies

TNF, IL-2 increased; IL-4, IL-10 decreased

Small-fiber neuropathy

IL-6, IL-8 increased locally in affected skin

Complex regional pain syndrome

TNF, IL-6 increased; IL-1RA decreased locally in skin

IL-6, IL-8, MCP1 increased in CSF

Fibromyalgia syndrome

IL-6 increased; fractalkine, IL-17A, IL-4, IL-10 decreased

Back pain and sciatica

IL-1ß, IL-6, TNF, CCL-2 increased; TNF, IL-1ß in CSF correlate with pain scores

Chronic pelvic pain syndrome

CCL2, CCL3

CSF= cerebrospinal fluid.

(a) Measurement in whole blood or serum, unless otherwise stated.

Note: See text for related references.

Interleukin Family

The IL family examined in this section includes IL-1ß, IL-2, IL-6, IL-17, IL-4, IL-13, and IL-10.

Interleukin 1ß

The IL-1 family comprises 11 members (IL-1α and -ß, IL-1Ra [IL-1 receptor antagonist], IL-18, IL-33, variants of IL-36 and IL-36Ra, IL-37 and IL-38) and 10 consecutively numbered receptors (Dinarello, 2018). This family is prototypical of unspecific innate immunity. IL-1 receptors have high homology with TLRs and mediate basic inflammatory responses, such as the induction of cyclooxygenase type 2 (COX-2) and the production of multiple cytokines and chemokines (Dinarello, 2018). IL-1ß is algesic in all models tested, and IL-1 antagonism has been extensively studied in RA.

The group of Sergio Ferreira first identified IL-1ß as a mediator of inflammatory hyperalgesia in the periphery (Ferreira, Lorenzetti, Bristow, & Poole, 1988). Others focused on the role of cytokines in the CNS, mostly in the spinal cord, and identified glial cells as the most important players in central hyperalgesia. Interestingly, some of the early studies of cytokines and pain found analgesic actions of high doses of a pro-inflammatory cytokine, where low doses were analgesic (Hori, Oka, Hosoi, & Aou, 1998; Nakamura, Nakanishi, Kita, & Kadokawa, 1988). IL-1β inhibitors applied either locally or intrathecally in nerve injury models reduced pain behavior (Sommer, Petrausch, Lindenlaub, & Toyka, 1999; Winkelstein, Rutkowski, Sweitzer, Pahl, & DeLeo, 2001). Mice deficient in the IL-1 receptor did not develop hyperalgesia after nerve injury; they also had reduced spontaneous activity in dorsal root axons compared to wild-type mice (Wolf, Gabay, Tal, Yirmiya, & Shavit, 2006). Mice deficient in both IL-1β and IL-1α had significantly reduced mechanical hypersensitivity in peripheral nerve injury models (Honore et al., 2006).

In models of painful nerve injury, like CCI of the sciatic nerve, IL-1ß is one of the cytokines most rapidly (within hours) upregulated in the damaged nerve and in the dorsal DRG. Unilateral CCI also increases IL-1ß in the contralateral homologous nerve, mediated by NMDA receptors (Kleinschnitz, Brinkhoff, Sommer, & Stoll, 2005). In many neuropathic pain models, TNF, IL-1ß, and IL-6 mRNA and protein levels were found to be increased in the lumbar spinal cord of rats and mice. Later, it was found that this finding was more consistently linked to pain in male rodents than in females (Sorge et al., 2011), concordant with reduced central cytokine upregulation in females (Üçeyler et al., 2008) and a response to cytokine inhibition in pain only in the male animals (Taves et al., 2016).

Interleukin 1β sensitizes C fibers in rat knee joints to mechanical stimuli but reduces activity of A-delta fibers (Ebbinghaus et al., 2012). In a skin–nerve in vitro preparation, brief exposure to IL-1β resulted in facilitation of heat-evoked CGRP release from peptidergic neurons (Opree & Kress, 2000). The short response latency and the absence of the neuronal cell soma in the preparation indicated that the heat sensitization was independent of changes in gene expression or receptor upregulation. Further experiments showed that IL-1β can act directly on sensory neurons to increase their sensitivity to noxious heat via a mechanism involving IL-1 receptor I, tyrosine kinase, and PKC (Obreja, Rathee, Lips, Distler, & Kress, 2002). IL-1ß applied intraperitoneally increased the sensitivity to noxious heat in rats, and the IL-1 receptor antagonist (IL-1Ra) blocked lipopolysaccharide (LPS)– and lithium-induced hyperalgesia (Maier, Wiertelak, Martin, & Watkins, 1993; Watkins et al., 1994). Intraneural injection of IL-1ß in rats at physiological doses induced signs of neuropathic pain (Zelenka, Schafers, & Sommer, 2005). A thorough mechanistic study using patch-clamp recordings in lamina II neurons of isolated spinal cord slices showed that IL-1ß enhanced the frequency and amplitude of spontaneous excitatory post synaptic currents (EPSCs) and reduced the frequency and amplitude of spontaneous inhibitory post synaptic currents IPSCs, enhancing AMPA- or NMDA-induced currents, and IL-1ß suppressing GABA- and glycine-induced currents (Kawasaki, Zhang, Cheng, & Ji, 2008). Direct activation of nociceptors by IL-1ß was further shown to be mediated by p38 MAPK and to increased nociceptor excitability by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels (Binshtok et al., 2008). Furthermore, IL-1ß suppressed voltage-gated K+ channels (Maier et al., 1993) and increased TRPV1 currents (Obreja et al., 2002). In the superficial dorsal horn, IL-1β enhanced LTP at C-fiber synapses, partly through phosphorylation of NMDA receptors (T. Liu, Jiang, Fujita, Luo, & Kumamoto, 2013).

Interleukin 2

Interleukin 2 is a 15-kDa opioid-like protein primarily produced by CD4+ T cells, part of the γ-receptor chain family that also includes IL-4, IL-7, IL-9, IL-15, and IL-21, all of which use a JAK/STAT receptor pathway. It acts via three Class I receptors with low, intermediate, and high affinity to IL-2. As a pleiotropic cytokine, its most important function is to serve as a survival factor for regulatory T (T-reg) cells. Low-dose IL-2 specifically can control autoimmune diseases and inflammation by expanding and activating T-reg cells (Klatzmann & Abbas, 2015).

Both pro- and analgesic effects have been described for IL-2. Interestingly, IL-2 was one of the first cytokines observed to induce pain in humans, which was then a side effect of antitumor trials (Wallace, Margolin, & Waller, 1988), although literature on Il-2 and pain has since been sparse compared to other cytokines. IL-2 is elevated in the serum of rats after a sciatic nerve crush lesion. Intraplantar injection of IL-2 and IL-2–expressing vectors produced antihyperalgesia (Yao et al., 2002). Application of IL-2 directly into the locus coeruleus also inhibited pain behavior. Interestingly, adoptive transfer of T-reg cells via intrathecal injection relieved mechanical allodynia in a chemotherapy model in mice (Duffy, Keating, Perera, & Moalem-Taylor, 2018), such that the IL-2 effect in analgesia might be related to the action on T-regs.

Interleukin 6

Interleukin 6 family cytokines use the common signaling receptor subunit gp130 (Rose-John, 2018). Other IL-6 family members are IL-11, IL-27, IL-35, cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). All these cytokines need the gp130 subunit and an additional receptor subunit to exert their actions. In the case of IL-6, this is the IL-6R, and in the case of CNTF, for example, the CNTF-R, but there is considerable overlap of receptor binding (Rose-John, 2018). Binding of IL-6 to the IL-6R induces so-called classical signaling with signal transduction via JAK/STAT3, MAPK, and phosphoinositide 3-kinase pathways, mediating mainly anti-inflammatory and regenerative responses (Rose-John, 2018). In contrast, IL-6 rans-signaling via binding to extracellular soluble IL-6 R and membrane-bound gp130 is pro-inflammatory (Rose-John, 2018).

Intracerebral ventricular interleukin-6 in mice reduces latencies for nocifensive behavior in the hot plate test (Oka, Oka, Hosoi, & Hori, 1995). Conversely, IL-6 KO mice show reduced pain responses in some, but not in all, studies (Ramer, Murphy, Richardson, & Bisby, 1998; Xu et al., 1997). The results have to be interpreted with care because IL-6 KO mice may have a markedly increased production of TNF. Intrathecal injection of anti–IL-6 antibodies attenuated mechanical allodynia in a spinal nerve injury model (Arruda, Sweitzer, Rutkowski, & DeLeo, 2000).

The application of combined IL-6 and its soluble receptor sIL-6R into the knee joint of rats increased the responses of spinal neurons to mechanical stimulation not only of the knee but also of other parts of the leg, indicating an expansion of the receptive field of the neurons and possibly central sensitization. This has been considered an explanation for the finding that spinally applied soluble gp130 did not reverse established hyperexcitability of joint nociceptors (Schaible, 2014).

The IL-6/gp130 ligand–receptor complex induces heat hypersensitivity both in vitro and in vivo. This process is mediated by activation of PKCδ and subsequent regulation of TRPV1 (Andratsch et al., 2009). Similar findings were reported for OSM. In mice with a conditional deletion of gp130 in nociceptors, the phase of mechanical hypersensitivity induced by tumor, nerve injury, or inflammation was shortened, identifying the IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity in these conditions (Quarta et al., 2011). In a rat bone cancer model, treatment with soluble gp130, an IL-6/sIL-6R trans-signaling inhibitor, attenuated hyperalgesia and the overexcitability of DRG neurons. TRPV1 was the downstream target, supporting the IL-6/JAK/PI3K/TRPV1 signaling cascade (Fang et al., 2015). IL-6 also potentiated spontaneous and stimulus-evoked activity in DRG neurons cultured in multiwell microelectrode arrays (Black et al., 2018).

Interleukin 17

The IL-17 family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17A is the best studied in the context of pain (Taams, Steel, Srenathan, Burns, & Kirkham, 2018). IL-17 is produced by CD8+ T cells, γδ T cells, and other immune cells. Its expression is regulated by pro-inflammatory cytokines. Interest in IL-17 increased with the discovery of Th17 T cells, a CD4+ T cell lineage distinct from Th1 and Th2 cells. The IL-23–IL-17 axis is regarded as a pivotal pathway in host protection and inflammation (Taams et al., 2018). IL-17 increases the transcription of pro-inflammatory cytokines and chemokines, but it also has direct effects on nociceptors.

In sciatic nerve CCI in mice, there was a monophasic expression of IL-17A in degenerating nerves at Day 7 after CCI, and transcripts for the IL-17A regulatory cytokines IL-23 and IL-15 peaked earlier. RAG-1 (recombinant activating gene) KO mice lacking functional T lymphocytes did not express IL-17A mRNA in distal nerve segments following CCI and had less thermal hyperalgesia, indicating a role for this cytokine and its downstream mediators in pain (Kleinschnitz et al., 2006). Also, intra-articular injection of IL-17 caused hyperalgesia and a dose-dependent increase in C-fiber responses to joint rotation (Pinto et al., 2010), and IL-17 KO mice had reduced mechanical hyperalgesia in an arthritis model (Segond von Banchet et al., 2013). In the model of antigen-induced arthritis, mechanical hyperalgesia did not occur in IL-17 KO mice, while the inflammation was similar to wild-type mice (Ebbinghaus et al., 2017). Mechanisms of IL-17A action include phosphorylation of protein kinase B (PKB/Akt) and extracellular-regulated kinase (ERK), upregulation of TRPV4 (Schaible, 2014), and increase of tetrodotoxin-resistant sodium channels with generation of action potentials in DRG neurons (Ebbinghaus et al., 2017).

In a mouse model of chronic pelvic pain, an IL-17 receptor antagonist reduced pain in the chronic phase, but not in the acute phase. IL-17 antibody also attenuates the hyperalgesia induced by intrathecal application of the chemokine CXCL13, concomitant with reducing trafficking of the NMDA receptor in the synaptic processes of long-term potentiation (Zhu, Yuan, Yu, Jia, & Sun, 2017).

Interleukins 4 and 13

Interleukin 4 and IL-13 share the same receptor system and signal predominantly through STAT6 (Karo-Atar, Bitton, Benhar, & Munitz, 2018). They regulate Th2-mediated immune responses and have been extensively studied in atopic diseases, including asthma, but have recently been found of interest in metabolism, tissue regeneration, cancer, and learning and memory. Both IL-4 and IL-13 inhibit inflammatory cytokine production. They bind to combinations of subtypes of IL-4 and IL-13 receptors, which explains some overlapping and some nonredundant functions (Karo-Atar et al., 2018).

In most animal models, IL-4 is analgesic. It reduces the acetic acid–induced writhing response in mice and the zymosan-induced knee joint incapacitance of rats, and IL-4 gene therapy attenuates mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation in mice (Hao, Mata, Glorioso, & Fink, 2006). Intrathecal application of recombinant IL-4 suppresses mechanical hypersensitivity in rats with nerve injury (Okutani, Yamanaka, Kobayashi, Okubo, & Noguchi, 2018). IL-4 links the immune system to the opioid system by inducing the transcription of mu- and delta-opioid receptors (Kraus, 2009). On the other hand, IL-4 transcription in T cells can be stimulated by endogenous and exogenous opioids (Börner, Lanciotti, Koch, Hollt, & Kraus, 2013). However, there is no direct evidence that the analgesic effect of IL-4 is mediated through opioid signaling, but some evidence does show inhibition of the release of pro-inflammatory cytokines (Hao et al., 2006). IL-4–deficient mice have spontaneous tactile allodynia, in accordance with increased responses to von Frey filaments in wide dynamic range neurons (Lemmer et al., 2015). IL-10 and IL-13 are upregulated in the ipsilateral spinal cord of IL-4 KO mice after nerve injury, possibly explaining why there is no genotype difference in pain behavior after CCI (Lemmer et al., 2015). Unexpectedly, CCI induces gene expression of mu, kappa, and delta opioid receptors in the contralateral cortex and thalamus of IL-4 KO mice, which was paralleled by fast onset of morphine analgesia. The complex regulation behind these findings still needs to be explored (Üçeyler, Topuzoglu, Schiesser, Hahnenkamp, & Sommer, 2011). In mice with a sciatic nerve crush injury, treadmill running reduces pain behavior and restores IL-4 (and IL-1Ra and IL-5) to preinjury levels in nerve and spinal cord tissue (Bobinski, Teixeira, Sluka, & Santos, 2018).

Interleukin 10 Family

Interleukin 10 was originally described as “cytokine synthesis inhibitory factor” because it inhibits production of cytokines by activated T cells and macrophages and thus belongs to the anti-inflammatory (Th2) cytokines. The IL-10 family includes IL-19, IL-20, IL-22, IL-24, and IL-26 (Walter, 2014). The production of IL-10 is inhibited by several cytokines, such as IL-4, IL-13, and IFN-γ and through autoregulation by IL-10 itself. To be active, IL-10 requires the assembly of the IL-10R1 and IL-10R2 chains. Blockade of IL-10 signaling leads to severe inflammatory disease, as in children with early onset inflammatory bowel disease (Glocker, Kotlarz, Klein, Shah, & Grimbacher, 2011). In pain models, IL-10 has mostly been shown to produce analgesic effects.

Interleukin 10 pretreatment reduced the hyperalgesic responses to intraplantar injections of carrageenan, IL-1β, IL-6, and TNF-α (Poole, Cunha, & Ferreira, 1999). Systemic IL-10 downregulated local levels of IL-1β, TNF-α, and NGF after endotoxin injection into the hind paw and reduces thermal and mechanical hyperalgesia. The intrathecal injection of IL-10 protein, of IL-10 DNA via viral vectors, and of naked DNA attenuated hyperalgesia after CCI (Milligan et al., 2006). In painful experimental nerve injury, IL-10 was downregulated and recovered slowly. Treatment with thalidomide attenuated pain behavior and accelerated restoration of IL-10 levels (George et al., 2004).

Tumor Necrosis Factor Family

The TNF ligand and receptor superfamilies consist of a large number of structurally related proteins, including 19 ligands and 29 receptors (Vanamee & Faustman, 2018). TNF is a pleiotropic pro-inflammatory cytokine produced by a wide variety of cells; it exists in a 26-kDa transmembrane and in a 17-kDa secreted form, both of which are biologically active.

The role of TNF in pain and the potential underlying mechanisms has been extensively studied in animal and cellular models. Mice deficient in the TNF receptors I and II develop less sensitization after nerve injury (Vogel, Stallforth, & Sommer, 2006). Subcutaneous injection of TNF lowers mechanical activation thresholds in C nociceptors of rat nerves. Perfusion of TNF onto rat DRG in vitro elicited neuronal discharges in A and C fibers, more so after nerve injury, indicating an increased sensitivity of injured afferent neurons to TNF (Schäfers, Lee, Brors, Yaksh, & Sorkin, 2003). Subthreshold quantities of TNF, injected into a DRG at the same time that its spinal nerve was ligated, resulted in faster onset of allodynia and increased spontaneous pain behavior compared to nerve ligation alone. DRG neurons with injured afferents, as well as neighboring neurons attached to intact afferent fibers running within the same peripheral nerve, had increased immunoreactivity for and increased sensitivity to TNF (Schäfers, Geis, Svensson, Luo, & Sommer, 2003).

Injection of TNF into normal rat knee joints caused a dose-dependent increased activity of C fibers to innocuous and noxious rotation of the joint (Richter et al., 2010). Endogenous TNF, produced in rat sciatic nerve after nerve injury, was transported anterogradely to muscle, and intramuscular injection of TNF induced muscle hyperalgesia (Schäfers, Sorkin, & Sommer, 2003) responsive to treatment directed at reducing nerve excitability. Thus, there is strong in vivo and in vitro evidence that injury results in increased endogenous TNF, that injured nerve fibers are sensitized to the excitatory effects of TNF, and that TNF may sensitize nociceptors via actions on TRP and sodium channels. An acute TNF-induced decrease in K+ conductance may be one of the pathophysiological factors.

A role of TNF in central sensitization has also been identified. Peripheral inflammation induced TNF-dependent movement of glutamate receptor 1 into neuronal membranes in the spinal cord (Choi, Svensson, Koehrn, Bhuskute, & Sorkin, 2010). The intracellular protease caspase 6 (CASP6) was released from the terminals of primary afferents and induced microglial TNF secretion in the spinal cord, hypersensitivity, and synaptic potentiation (Berta et al., 2014). TNF, like IL-1 and IL-6, regulated synaptic activity in the superficial spinal cord by enhancing transmission via excitatory neurotransmitters, while decreasing inhibitory transmission (Kawasaki et al., 2008; L. Zhang et al., 2011). Region-dependent synaptic changes in the spinal cord and brain were later confirmed and attributed to TNF-R1.

Anti-TNF treatment, including anti-TNF antibodies, TNF-soluble receptors, and recombinant TNFR-Fc fusion proteins reduced hyperalgesia in neuropathic pain models (Sommer et al., 2001). Prophylactic treatment with antibodies to TNF prevented signs of the neuropathy caused by bortezomib (Ale et al., 2014). Etanercept attenuated neuropathic pain in diabetic mice and spinal cord injury pain in rats (Clark, Old, & Malcangio, 2013). Lentivirus-mediated silencing of TNF in DRG relieved neuropathic pain and reduced neuronal cell death in mice with L5 nerve transection (Ogawa et al., 2014). The blocking studies were most successful when the anti-TNF agents were given preemptively, in accordance with the very early peak in TNF expression after injury (Üçeyler et al., 2008).

The Chemokine Superfamily

The nomenclature of the chemokine superfamily is based on the number and spacing of conserved cysteine residues, leading to the CXC, CC, CX3C, and C subfamilies.

CCL-2 or MCP-1 is a potent chemoattractant and activator of monocytes, activated T cells, natural killer (NK) cells, and eosinophils. It activates the receptors CCR2 and CCR11. CCL2 can be released from nociceptors like a neurotransmitter and is thus involved in nociceptive signal processing in the spinal cord, where it has been shown to influence neuropathic pain via the interaction of astrocytes and neurons and by increasing NMDA-induced currents (R. G. Xie et al., 2018). Following peripheral nerve compression injury, CCR2 signaling directly excited subsets of sensory neurons (Sun, Yang, Donnelly, Ma, & LaMotte, 2006). One mechanism may be by increasing current density of the sodium channel Nav1.8 and decreasing inactivation (Belkouch et al., 2011). CCL2 is involved in opening the blood–spinal cord barrier after peripheral nerve injury, which contributes to local inflammation in the spinal cord (Echeverry, Shi, Rivest, & Zhang, 2011). Mice deficient in CCR2 exhibited impaired neuropathic pain response following spared nerve injury (Abbadie et al., 2003), while glial overexpression of CCR2 led to enhanced nociceptive responses. A CCR2 receptor antagonist has been shown to reverse tactile hyperalgesia, where neuronal excitation by CCR2 may in part be mediated via TRPV1 and TRPA1 present on sensory nerves (Jung, Toth, White, & Miller, 2008).

CCL5, or RANTES, is a CC chemokine with chemotaxic effects on monocytes, macrophages, microglia, T cells, eosinophils, basophils, as well as developing DRG neurons via the chemokine receptors CCR1, CCR3, and CCR5 (Bolin et al., 1998). RANTES can also produce rapid release of histamine from basophils (Meucci et al., 1998). In HIV-1–associated painful peripheral neuropathies, both RANTES and the viral coat protein for HIV-1, gp120, produced intracellular Ca+ fluxes in sensory neurons through the HIV-1 coreceptor CCR5 (Bhangoo, Ripsch, Miller, & White, 2008; Oh et al., 2001).

Macrophage inflammatory protein 1α (MIP1α, CCL3) is an 8-kDa member of the CC chemokine family that regulates cellular recruitment, trafficking of leukocytes, and host responses. It binds with high affinity to the chemokine receptors CCR1, CCR3, and CCR5 (Saeki & Naya, 2003). Intrathecal injection of antibodies neutralizing CCL3 prevented pain behavior induced by nerve injury in rats. Mice lacking the cognate CCR5 did not develop pain behavior after nerve injury (Z. J. Zhang, Jiang, & Gao, 2017).

Fractalkine (CXCL1), the only member of the CX3C chemokine family, is constitutively expressed in the normal PNS and CNS, including neurons. It exists as a membrane-bound (large) and soluble (small) form; the latter is generated by cleavage from the membrane by metalloproteases. In its soluble form, fractalkine acts as a chemotactic cytokine, in the membrane bound form as a binding molecule (W. Liu et al., 2016). There is only one known receptor of fractalkine, CX3CR1, which is specific for this chemokine and is constitutively expressed on microglial cells. The intriguing mechanism is a function like a neurotransmitter, by which fractalkine is cleaved from neurons and activates glial cells by binding on their receptors. This may also explain the topographic specificity, for example, of microglial recruitment in the territory of an injured nerve (Scholz & Woolf, 2007). Others have shown activation of satellite cells in the DRG in inflammatory pain (Scholz & Woolf, 2007). In inflammatory and neuropathic pain models, fractalkine expression on microglia was increased. Exogenous application of fractalkine produced pain behavior in rats, and neutralizing antibodies to CX3CR1 attenuated pain behavior (Milligan, Sloane, & Watkins, 2008). In contrast, intraneural administration of fractalkine inhibited nociceptive behavior following spared nerve injury, and CX3CR1-deficient mice displayed more allodynia after SNI (Milligan et al., 2008).

Cytokines in Patients with Chronic Pain

Studies in patients can measure a range of cytokines in biomaterial and cross-sectionally or longitudinally compare the data to measures of pain. In these types of studies, conclusions on a causal relationship can only be drawn with care. Alternatively, a cytokine inhibitor can be used, to treat either the underlying disease or the pain itself.

Arthritis

In RA, anticytokine therapy has been successfully developed to be both disease modifying and analgesic (Schaible, 2014). Cytokines are also involved in OA and in spondyloarthritis. Arthritis pain is prototypical in that patients may suffer from a combination of spontaneous pain and evoked pain on movement or palpation of the joint, which is reduced, for example, by blockade of the IL-1R (Cardiel et al., 2010). This hyperalgesia is attributed to sensitization of the joint nociceptors, and there is ample evidence from experimental and human studies that cytokines have a major role here (Schaible, 2014). While the biologicals used to treat arthritis are disease modifying in the sense that they reduce the underlying inflammation, their effects on pain may be partially independent from this. For example, infliximab, a TNF-neutralizing antibody, reduced arthritis pain within 1 day, which is before infliximab can act on the disease process itself. Tocilizumab, a recombinant humanized monoclonal antibody against the IL-6 receptor, also led to a rapid reduction in pain scores in RA (Yazici et al., 2013).

Interleukin 17A levels are increased in the synovial fluid of patients with RA (Schaible, 2014). Monoclonal antibodies against IL-17 attenuated inflammatory diseases, and particularly in RA, an antibody to IL-17A reduced joint inflammation and joint pain. Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, was shown to rapidly reduce pain in psoriatic arthritis (McInnes et al., 2018). In ankylosing spondylitis, although sustained functional improvement was shown, direct effects on pain scores were minor (Marzo-Ortega et al., 2017; Pavelka et al., 2017).

Polyneuropathy

Polyneuropathies, diseases of the PNS, can be painful or painless, sometimes within the same etiological category as in diabetes or in the inflammatory neuropathies. This natural paradigm can be used to study whether patients with polyneuropathy with and without pain differ in blood or tissue cytokine levels.

In a prospective study, mRNA and protein levels of IL-2, TNF, IL-4, and IL-10 were measured in blood drawn from patients with painful neuropathy and compared to patients with painless neuropathy and to healthy controls. Patients with a painful neuropathy had about two-fold higher IL-2 and TNF mRNA and protein levels than patients with painless neuropathy. In contrast, the mRNA levels of the anti-inflammatory cytokine IL-10 were about two-fold higher in patients with painless neuropathy than in patients with painful neuropathy and controls (Üçeyler, Tscharke, et al., 2007). IL-4 protein levels were even 20-fold higher in patients with painless neuropathy than in healthy controls, but they were also 17-fold higher in patients with painful neuropathy than in controls. Thus, patients with painful neuropathy might have a pain-susceptible cytokine profile with an imbalance toward a pro-inflammatory profile. Similar trends, with increased TNF, RANTES, and osteoprotegerin, were found in painful compared to painless diabetic neuropathy (Doupis et al., 2009). However, these findings were not reproduced by all groups (Magrinelli et al., 2015), illustrating the heterogeneity of patient cohorts, the problems of small sample sizes, and differences in methodology.

It is conceivable that measuring cytokines directly in affected nerve or skin tissue might more accurately correlate with painfulness of the disease. However, when sural nerve and skin samples from 133 prospectively studied patients with neuropathies were assessed for gene expression of a number of pro- and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF, IL-10) and some neurotrophic factors, differences between neuropathy and healthy controls were scarce, and there was no clear difference between patients with or without pain (Üçeyler, Riediger, Kafke, & Sommer, 2015). Only IL-6 and IL-10 expression were higher in sural nerves from painful compared to painless neuropathies, and in skin, IL-6 and IL-10 gene expression was increased in patients in general compared to controls.

Small-fiber neuropathy (SFN) is a variant of sensory neuropathy characterized by spontaneous burning pain in the feet and hands. Most patients suffer from pain in the skin distally in the leg, and the proximal leg is pain free. When systemic and local cytokine gene expression profiles were analyzed compared to matched controls, gene expression of IL-2, IL-10, and TGF-β1 was mildly elevated in venous blood of the patients with SFN compared to controls. In length-dependent SFN, where intraepidermal nerve fiber density is reduced only in the skin of the lower leg and patients have distally accentuated pain, there was a 200- to 500-fold increase in local gene expression of IL-6 and IL-8 in affected distal skin compared to unaffected proximal skin (Üçeyler et al., 2010). However, the cohort was small, and of course, a causative connection between the cytokine expression and pain needs to be proven.

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is considered a consequence of exaggerated post-traumatic inflammation or insufficient resolution of inflammation, which makes a causative or secondary change in the cytokine profile quite likely. To assess local cytokines, the technique of analyzing the blister fluid from the affected extremity has been used. In a small study, TNF and IL-6 were increased in blister fluid (Huygen et al., 2002). One follow-up study collected blister fluid over up to 6 years from 12 patients with CRPS (Wesseldijk, Huygen, Heijmans-Antonissen, Niehof, & Zijlstra, 2008). IL-6 and TNF were elevated ipsilaterally in the first samples and normalized over time. In another study, bilaterally increased pro-inflammatory TNF and MIP-1ß were reported, with decreased anti-inflammatory IL-1Ra protein levels compared to patients without CRPS in the acute phase. After 6 months of analgesic treatment, the increased cytokine protein levels in patients with CRPS had changed back to the level of patients without CRPS (Lenz et al., 2013). The change was more prominent in those patients that had been treated with corticosteroids. Local cytokine expression has also been investigated in skin biopsies from patients with CRPS. Local TNF levels in affected skin, but not TNF levels in venous blood, were higher in patients with CRPS than in patients with bone fracture without CRPS or OA (Krämer et al., 2011).

In the cerebrospinal fluid (CSF) of 24 patients with chronic CRPS, IL-1ß and IL-6, but not TNF, were increased (Alexander, van Rijn, van Hilten, Perreault, & Schwartzman, 2005). The same group later confirmed elevated IL-6 and also the astrocyte protein glial fibrillary acidic protein and the chemokine MCP-1 in CSF of patients with CRPS, who further had low levels of the anti-inflammatory cytokines IL-4 and IL-10.

Studies using venous blood came to variable results. In 25 patients with early CRPS, IL-8 and the soluble TNF receptors I and II and the neuropeptide substance P, but not IL-6, were elevated (Schinkel et al., 2006). In a longitudinal study including disease controls, the same group later only confirmed the finding of an increase in the TNF receptors I and II (Schinkel et al., 2009). We found higher gene expression of TNF and IL-2 in patients with CRPS and reduced gene expression of IL-8, IL-4, and IL-10. Serum protein levels of TNF and IL-2 were increased, and those of IL-4, IL-10, and TGF-ß1 were reduced (Üçeyler, Eberle, Rolke, Birklein, & Sommer, 2007). Another study showed a higher percentage of the CD14+ CD16+ monocyte/macrophage subgroup in patients with CRPS, concomitant with lower IL-10 plasma levels (Ritz et al., 2011).

A meta-analysis concluded that CRPS was associated with a pro-inflammatory state in the blood, in blister fluid, and in CSF, with differences between acute and chronic CRPS (Parkitny et al., 2013). Taking all data together, acute CRPS seems to be characterized by an increased Th1/Th2 ratio, and both pro- and anti-inflammatory factors seem to be involved in the maintenance of chronic CRPS. The authors of the meta-analysis stressed the need for publishing clear details about the source, collection, and processing of samples; assay sensitivity; and management of samples that fall below the lowest detectable threshold values (Parkitny et al., 2013). These are excellent suggestions that would considerably increase quality in studies using human biomaterial.

The finding of a common trend toward an increase in pro-inflammatory cytokines and a lower expression of anti-inflammatory cytokines in patients with CRPS led to the first trials using TNF inhibitors in CRPS. After promising case reports, a RCT using the TNF inhibitor infliximab was prematurely discontinued due to recruitment problems, and no firm conclusions could be drawn (Dirckx, Groeneweg, Wesseldijk, Stronks, & Huygen, 2013).

Chronic Widespread Pain and Fibromyalgia

Patients treated with cytokines as adjuvant anticancer therapies had fibromyalgia-like symptoms (Wallace et al., 1988), which led to ideas about a role of cytokines in fibromyalgia-related pain. Since then, numerous studies have measured cytokines in serum, plasma, and CSF and in supernatant of stimulated white blood cells in patients with fibromyalgia. A systematic review including 25 studies revealed higher serum levels of IL-1Ra, IL-6, and IL-8 and higher plasma levels of IL-8 in patients with fibromyalgia (Üçeyler, Häuser, & Sommer, 2011). However, the overall methodological quality of studies was low; results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed.

In a cohort of patients with chronic widespread pain, of whom not all fulfilled the formal fibromyalgia criteria of the time because of negative tender points, lower gene expression and lower serum protein concentrations of the anti-inflammatory cytokines IL-4 and IL-10 in venous blood has been reported (Üçeyler et al., 2006). Later, numerous studies approached the question of cytokines, chemokines, and other inflammatory mediators in fibromyalgia, including IL-17A (Pernambuco et al., 2013). In both CSF and blood, among other inflammatory proteins, fractalkine and IL-8 were identified as major players (Backryd et al., 2017). A number of chemokines were increased in serum in another cohort. As in other painful disorders, it has been suggested that inflammatory mediators are relevant not in all, but probably in a subgroup of, patients with fibromyalgia, which might be an important factor for stratifying patients in clinical trials (Metyas, Solyman, & Arkfeld, 2015). A small study showed an increase in cytokine production from induced microglia-like cells from patients with fibromyalgia, but this finding needs to be confirmed with larger numbers of patients (Ohgidani et al., 2017).

Interventional studies would be more apt to support a causative link between cytokine profiles and disease than mere correlative studies, and few data are available for this. Exercise is one of the strongest stimulators of anti-inflammatory cytokine expression in healthy persons, but this connection appears to be disturbed in patients with fibromyalgia. However, IL-8 serum levels were reduced by long-term exercise in those with fibromyalgia (Bote, Garcia, Hinchado, & Ortega, 2014), and elevated IL-8 and TNF serum levels were normalized after 6 months of multidisciplinary pain therapy (Wang, Moser, Schiltenwolf, & Buchner, 2008).

Postherpetic Neuralgia

Because inflammation plays a role in acute herpes zoster, it has been hypothesized that persistent inflammation may be a causative factor in postherpetic neuralgia (PHN). Data on cytokine levels have been conflicting. Compared to controls, IL-1ß was increased in the CSF (Zhao et al., 2017). In a small cohort, we could not detect differences in cytokine expression between affected and unaffected skin and between patients and controls in serum (Üçeyler, Valet, Kafke, Tolle, & Sommer, 2014). One study showing that CSF IL-8 levels in patients with acute herpes zoster predicted the development of PHN has never been replicated (Kotani et al., 2004).

Low Back Pain

A systematic review including 10 studies of cytokines in nonspecific low back pain found moderate evidence for a positive association between serum IL-6 levels and symptom severity and a positive association between TNF levels and the presence of nonspecific low back pain (van den Berg et al., 2018). Cytokines and chemokines are also increased locally in herniated disks and in CSF, where they correlate with pain scores.

Clinical Trials with Drugs Affecting the Cytokine System

An indirect approach to assess the link between cytokines and nociception is to use a therapy that leads to analgesia and to monitor cytokine profiles over time. One study using spinal cord stimulation showed a decrease in cytokine levels in blister fluid after treatment, concomitantly with clinical improvement, but there was no control group, such that this could also have been the spontaneous course (Kriek et al., 2018). Transcutaneous electrical nerve stimulation (TENS), which in itself has a weak analgesic effect, reduced cytokine levels according to a recent meta-analysis (do Carmo Almeida et al., 2018).

High-quality data from clinical trials showing efficacy of anticytokine treatment in painful conditions are rare. The examples come from those conditions where cytokines are definitely involved in the pathophysiology of the disease. For example, IL-6 inhibitors alleviated pain in RA (Strand et al., 2018) and ocular inflammation (Silpa-Archa, Oray, Preble, & Foster, 2016). Antibodies to IL-6 and IL-6R have been successfully developed for the treatment of RA and other IL-6–driven diseases like Castleman disease and giant cell arteritis (Garbers, Heink, Korn, & Rose-John, 2018). Some open studies have shown success in reducing pain with cytokine inhibitors, like the anti-IL-6R monoclonal antibody tocilizumab, applied locally onto the spinal nerve in patients with back and leg pain due to lumbar spinal stenosis (Ohtori et al., 2012).

Similarly, TNF inhibitors reduced pain in RA (Maini et al., 1998; Moreland et al., 1997) and ankylosing spondylitis (Maxwell et al., 2015), but successful analgesia in other conditions needs to be demonstrated. There is a large preclinical literature on cytokines and their inhibition in models of disk herniation and low back pain (Ohtori, Inoue, Miyagi, & Takahashi, 2015). While systemic TNF blockade in humans was not successful, although it may reduce the need for surgery, local epidural or transforaminal application reduced pain in patients with low back pain or sciatica (Freeman et al., 2013; Sainoh et al., 2016). In CRPS, a case series with TNF inhibitors (Eisenberg, Sandler, Treister, Suzan, & Haddad, 2013) gave rise to a clinical trial, which, however, was not successful (Dirckx et al., 2013). A CCR2 antagonist was not successful in RCTs in painful diabetic neuropathy and post-traumatic nerve pain (Kalliomaki, Attal, et al., 2013; Kalliomaki, Jonzon, et al., 2013).

Given the limited success of the anticytokine treatment in analgesia, both upstream and downstream mediators have been explored. The p38 MAPK has strong preclinical data suggesting a role in cytokine regulation and pain, and numerous inhibitors have been developed over time. A short-term RCT with the p38 MAPK inhibitor dilmapimod showed an effect on pain scores in patients with different types of neuropathic pain (Anand et al., 2011). Another compound, losmapimod, was not successful in RCTs for peripheral nerve injury pain and lumbosacral radiculopathy (Ostenfeld et al., 2013, 2015).

The overwhelming preclinical evidence for an important role for cytokines in many types of chronic pain stands in stark contrast to the failure of most RCTs using compounds directed at cytokines, chemokines, and their receptors. There are many potential reasons for this translational failure, including species differences, heterogeneous and inadequate animal models, aspects of age and sex, poor CNS availability of the compounds, and high placebo effects in the trials. Still, the dual action of some cytokines, U-shaped dose–response curves, and redundancy of the cytokine system may also play a role, which stimulates the search for “master switches” that would simultaneously block the inflammatory reaction (or accelerate its resolution). While mechanisms of individual cytokines and their receptors acting on the nervous system may be of high scientific interest, clinical effects may require a more comprehensive approach, targeting groups of cytokines at the same time. Potential candidates on the one hand are the inflammasome, purinergic receptors like P2X7, and on the other hand the resolvins. The negative immune regulator B7H1 was a potent inhibitor of the late pro-inflammatory phase after nerve injury and also reduced nociceptor activity by additional mechanisms (G. Chen et al., 2017).

Conclusion

Numerous preclinical studies have shown an important role for cytokines and neurotrophins in pain. Pro-inflammatory cytokines and some members of the neurotrophin family can directly act on receptors expressed by neurons or act as chemoattractants for a cell signaling cascade that leads to nociceptor sensitization and strengthening of central excitatory synapses. In particular with cytokines, data derived from patient biomaterial have shown correlations of elevated cytokine levels and experience of pain, but many studies had methodological problems, small sample sizes, unclear selection criteria, inadequate or inhomogeneous assay techniques, and lack of appropriate controls. Future longitudinal studies and studies using interventions directed at the cytokines and neurotrophins may help to differentiate between causal and unspecific effects and provide new promising avenues for targeted analgesic therapies.

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