• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Neurotherapeutics. Author manuscript; available in PMC Oct 5, 2010.
Published in final edited form as:
PMCID: PMC2950097
NIHMSID: NIHMS213544

Targeting Astrocyte Signaling for Chronic Pain

Summary

Clinical management of chronic pain after nerve injury (neuropathic pain) and tumor invasion (cancer pain) is a real challenge due to our limited understanding of the cellular mechanisms that initiate and maintain chronic pain. It has been increasingly recognized that glial cells, such as microglia and astrocytes in the central nervous system play an important role in the development and maintenance of chronic pain. Notably, astrocytes make very close contacts with synapses and astrocyte reaction after nerve injury, arthritis, and tumor growth is more persistent than microglial reaction and displays a better correlation with chronic pain behaviors. Accumulating evidence indicates that activated astrocytes can release proinflammatory cytokines (e.g., IL-1β) and chemokines (e.g., MCP-1/CCL2) in the spinal cord to enhance and prolong persistent pain states. IL-1β can powerfully modulate synaptic transmission in the spinal cord by enhancing excitatory synaptic transmission and suppressing inhibitory synaptic transmission. IL-1β activation (cleavage) in the spinal cord after nerve injury requires the matrix metalloprotease-2 (MMP-2). In particular, nerve injury and inflammation activate the c-Jun N-terminal kinase (JNK) in spinal astrocytes, leading to a substantial increase in the expression and release of MCP-1. MCP-1 increases pain sensitivity via direct activation of NMDA receptors in dorsal horn neurons. Pharmacological inhibition of the IL-1β, JNK, MCP-1, or MMP-2 signaling via spinal administration has been shown to attenuate inflammatory, neuropathic, or cancer pain. Therefore, interventions in specific signaling pathways in astrocytes may offer new approaches for the management of chronic pain.

Keywords: Neuropathic pain, nerve injury, spinal cord, cytokine, chemokine, MAP kinase, glia

INTRODUCTION

Pain is an unpleasant sensory experience and normally plays a protective role by warning us about potential harm to our body and enabling us to quickly remove the body part from noxious stimuli and further learn to avoid them in the long run. Upon noxious peripheral stimulation, pain information is mainly transmitted by thin myelinated Aδ fibers and unmyelinated C fibers to the dorsal horn in the spinal cord, where second order nociceptive neurons are activated by neurotransmitters, such as glutamate and neuropeptides [e.g., substance P (SP) and calcitonin gene-related peptide (CGRP)] that are released from the primary afferents.1 The information is further relayed to the thalamus, and finally reaches to the parietal lobe of cerebral cortex for pain perception.2, 3 This type of pain is transient and referred to as acute or physiological pain.

However, under injury conditions pain can be dissociated from its normal physiological role. It can persist for months to years, even after the original injury or inflammation has largely healed. This type of pain is called chronic or pathological pain, as the consequence of damage or dysfunction of the peripheral nervous system (PNS) and central nervous system (CNS) (neuropathic pain), peripheral tissue damage or inflammation (inflammatory pain), and tumor invasion (cancer pain).46 Chronic pain does not convey any useful information. Under injury conditions, painful pressure and thermal stimuli are grossly amplified (hyperalgesia). Even light touch is perceived painful (allodynia). Chronic pain creates considerable suffering for people affected, and is extremely costly for the individual and for the community; the estimated cost in the United States alone is over $100 billion every year7.

Chronic pain is a maladaptive pain, resulting from the development of neural plasticity in the PNS (peripheral sensitization) and CNS (central sensitization).810 It was generally believed for a long time that only neurons and their neural circuits were responsible for the development and maintenance of chronic pain, which led to the development of current therapeutics that have been focusing on neuronal targets, including drugs such as N-methyl-D-aspartic acid (NMDA) receptor antagonists, selective serotonin/norepinephrine reuptake inhibitors, opioid analgesics, and sodium channel blockers. Although these drugs have shown some effects in some patients,11 they often produce a brief pain relief via transient blockade of neurotransmission. Notably, the side effects of these drugs, often CNS-related, such as nausea, sedation, drowsiness, dizziness, as well as development of analgesic tolerance and addiction after opioid treatment, have greatly limited their universal use.11, 12 Therefore, research on other means of chronic pain treatment is in an urgent demand. As a consequence, studies on non-neuronal cells, especially glial cells in chronic pain conditions, have increased exponentially in the last decade.

Glial cells are 10 to 50 times as numerous as neurons and consist of three major groups: astrocytes, microglia, and oligodendrocytes.13 Microglia are the resident macrophage-like cells of the CNS. Oligodendrocytes, which are derived from neuroectoderm, produce myelin to enshealth neuronal axons. Astrocytes are the most abundant cells in term of their number and volume and constitute 40–50% of all glial cells.14 In normal conditions, microglia and astrocytes are relatively resting or quiescent (but see15). After injury or under disease conditions, they can be converted to reactive states and participate in the pathogenesis of neurological disorders.1618 Increasing evidence has shown that microglia and astrocytes play important roles in the development of chronic pain.1827 Unlike microglia and oligodendrocytes, astrocytes form networks with themselves and are closely associated with neurons and blood vessels. It is estimated that a single astrocyte enwraps 4–6 neuronal somata and contacts 300–600 neuronal dendrites.28 A close contact with neurons and synapses makes it possible for astrocytes to support and nourish neurons, and regulate the external chemical environment of neurons during synaptic transmission. In this review, we will discuss recent progress on astrocyte control of pain.

ASTROCYTE ACTIVATION IN PERSISTENT PAIN CONDITIONS

Glia activation is emerging as a powerful concept for understanding cellular mechanisms underlying chronic pain. Unfortunately, the term “glia activation” is poorly defined. In the pain research field, astrocyte activation is often referred to GFAP upregulation and astrogliosis (hypertrophy of astrocytes, as manifested by enlarged cell bodies and thick processes). The active astrocytes with gliosis are also called reactive astrocytes. Thus, in the following discussion we refer to this activation state as the reactive state, in order to separate from other activation states. It is well known that after peripheral nerve injury or inflammation or tumor invasion, astrocytes in the CNS especially the spinal cord undergo various biochemical, translational, transcriptional, and morphological changes. Therefore, astrocytes could display various activation states after peripheral sensory stimuli and injury. Some activation states occur within minutes, such as increases in intracellular Ca2+ and phosphorylation of signaling molecules. Some activation states occur after tens of minutes (e.g., translational regulation) and hours (e.g., transcriptional regulation). Other activation states may occur after hours or even days, such as astrocyte hypertrophy or astrogliosis.

Astrocyte reaction (GFAP upregulation and hypertrophy) has been found in various injury conditions that are associated with enhanced pain states. These conditions include (a) peripheral nerve injury such as chronic constriction injury (CCI),29 spinal nerve ligation (SNL, Fig. 1),30, 31 and infraorbital nerve ligation,32, 33 (b) tissue injury/inflammation produced by intraplantar injection of complete Freund's adjuvant,34 formalin,35 zymosan,35 and (c) tumor growth in the skin3638 and bone marrow.3941 While astrocyte reaction can occur at supraspinal areas, such as the rostral ventramedial medulla after chronic constriction injury of the rat infraorbital nerve,32, 33 the forebrain after CFA injection,34 the gracile nucleus after partial sciatic nerve ligation,42 most studies focus on the spinal cord dorsal horn.19

Figure 1
Spinal nerve ligation (SNL) induces a substantial increase in JNK phosphorylation and GFAP expression in astrocytes in the spinal cord dorsal horn

Notably, astroglial reaction after nerve injury is more persistent than microglial reaction (e.g., upregulation of the microglial markers CD11b/OX-42 and Iba-1 and hypertrophy of mciroglia). Astroglial reaction can last more than 150 days after nerve injury.43 In most cases, microglial reaction precedes astrocytic reaction34, 44, 45 and is likely to lead to astrocyte reaction.46 Interestingly, nerve injury induces an increase in IL-18 and IL-18 receptor in reactive microglia and astrocytes, respectively, in the dorsal horn, suggesting an interaction between microglia and astrocytes in neuropathic pain.47 However, astrocyte reaction is not always preceded by microglial reaction. Hald et al40 showed that bone cancer resulted in marked spinal astroglial reaction without microglial reaction.

It has been shown that GFAP expression after inflammation or nerve injury requires NMDA receptor48, 49 and neuronal activity.32, 49 GFAP expression is also critical for morphological changes of astrocytes (astrogliosis)34, 35 and often correlated with enhanced pain states,29, 30, 50 (but see31). Although intrathecal GFAP antisense oligonucleotide treatment in nerve injured animals was shown to reduce neuropathic pain behaviors,51 this contribution of GFAP to chronic pain could be indirect via unknown mechanisms. It is generally believed that astrocytes control pain states by producing neuromodulators/pain mediators, such as cytokines, chemokines, and growth factors,22, 32, 33, 52, 53 (also see discussion below). The production and release of these mediators are not directly controlled by GFAP, rather by some key intracellular signaling pathways, such as the MAP kinase pathway. Remarkably, nerve injury and inflammation induce a persistent phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes, which may represent a different activation state of astrocytes that is not only correlated with pain hypersensitivity but also an underlying cause of this hypersensitivity (Fig. 1).31, 5456

ASTROCYTES CONTRIBUTE TO ENHANCED PAIN STATES

Several lines of evidence suggest that activated astrocytes are sufficient to produce chronic pain symptoms. Hofstetter et al. reported that implantation of neural stem cells into the injured spinal cord causes allodynic-like hypersensitivity of the forepaws, which is mainly attributed to the conversion of the stem cells into astrocytes.57 Indeed, the allodynia is prevented when the neural cells are transfected with neurogenin-2 before transplantation to suppress the generation of astrocytes.57 Davies et al. demonstrated that transplantation of GRP (glial-restricted precursor)-derived astrocytes promotes the onset of mechanical allodynia.58 In particular, our recent data showed that intrathecal injection of TNF-α-activated astrocytes is sufficient to induce the chronic pain hall-mark, mechanical allodynia, in naïve animals by releasing the chemokine CCL2.59

Further studies indicate that astrocytes are also required for the generation of persistent pain. Fluoroacetate and its metabolite fluorocitrate are general inhibitors for glial cells especially astrocytes. Low doses of fluorocitrate specially disrupt astrocytic metabolism by blocking the glial-specific enzyme aconitase. Intrathecal injection of fluorocitrate or fluoroacetate has been shown to alleviate pain behaviors in animal models of inflammatory pain, neuropathic pain and postoperative pain.6065 Of interest fluorocitrate fails to inhibit muscle pain, a pain condition that does not show obvious glial reaction.66 L-alpha-aminoadipate (L-α-AA) is another relative specific cytotoxin for astrocytes.6769 Intrathecal injection of L-α-AA produces a dose-dependent attenuation of nerve injury-induced mechanical allodynia.31, 70

There is an increasing list of signaling molecules in astrocytes that have been implicated in persistent pain (Table 1). The glial glutamate transporter 1 (GLT-1) is abundantly expressed in astrocytes71 and contributes to the clearance of glutamate from synaptic clefts and the extracellular space.72, 73 The altered expression and function of glutamate transporters could modulate glutamatergic transmission74, 75 and neuronal plasticity such as long-term potentiation.76, 77 It has been demonstrated that nerve injury induces an initial increase78, 79 followed by a persistent decrease of GLT1 and GLAST in the spinal cord.7881 Inhibition of glutamate transporters causes an elevation in spinal extracellular glutamate concentrations and elicits spontaneous nociceptive behaviors and hypersensitivity to mechanical and thermal stimuli.82, 83 Gene transfer of GLT-1 into spinal cord has no effect on acute mechanical and thermal nociceptive responses in naive animals but attenuates inflammatory and neuropathic pain.84 These studies indicate a potential role of astroglial glutamate transporters in the recovery of chronic pain. However, the role of glutamate transporters in persistent inflammatory pain conditions could be different, since these transporters are not down-regulated after inflammation. Trigeminal pain following tooth pulp inflammation is attenuated by intrathecal superfusion of methionine sulfoximine, an inhibitor of the astroglial enzyme glutamine synthetase that is involved in the glutamate-glutamine shuttle.85

Table 1
Signaling molecules in astrocytes

Astrocytes express proteases such as tissue type plasminogen activator (tPA) and matrix metalloproteases (MMPs, see below) that may be critical for the cleavage and release of signaling molecules from astrocytes. tPA is an extracellular serine protease and converts the plasminogen into the serine protease plasmin. Kozai et al.86 showed that L4/5 root injury induces marked induction of tPA in activated astrocytes and a resultant increase of proteolytic enzymatic activity in the dorsal horn. Moreover, intrathecal administration of tPA inhibitor suppresses dorsal root ligation-induced mechanical allodynia. tPA-plasmin system may alter the excitability of dorsal horn neurons and pain transmission through the activation of growth factors87, 88 and modification of the NMDA receptors.89, 90

Astrocytes are characterized by forming gap junction-coupled networks, which could transmit Ca2+ signaling in the form of oscillations through the networks.91, 92 The major structural components of gap junctions are connexins. In the mammalian nervous system, at least six connexins (Cx26, Cx29, Cx30, Cx32, Cx36 and Cx43) have been identified. Among them, Cx30 and Cx43 are specifically expressed by astrocytes.93, 94 Interestingly, the expression of Cx43 increases markedly in response to facial nerve lesion,95 spinal cord injury,96 and CFA-induced inflammation,32 indicating a role of connexin in chronic pain. Inhibition of gap junction function by carbenoxolone— a nonselective gap junction inhibitor— produces analgesia in different pain models.9799 Particularly, intrathecal injection of carbenoxolone reduces sciatic nerve inflammation-induced mechanical allodynia in the contralateral paw, suggesting a role of astrocytes network and gap junction in the spread of pain beyond the injury site.98

In addition, astrocytes also express phosphorylated JNK and JNK1 (Fig. 1),31, 56 phosphorylated ERK,53, 100 endothelin receptor-B,101 TNF-α,33 bFGF (Fig. 2),102, 103 neurokinin-2 receptor,104 IL-18 receptor,47 IL-1β32, 33, 53, 100 and monocyte chemoattractant proetine-1 (MCP-1),52, 105 in response to nerve injury or inflammation. Importantly, pharmacological inhibition of these signaling molecules via spinal cord administration has been shown to reduce chronic pain symptoms (Table 1).

Figure 2
Spinal nerve ligation (SNL) induces a marked bFGF expression in spinal cord astrocytes

ASTROCYTES PRODUCE PROINFLAMMATORY CYTOKINES AND CHEMOKINES TO PROMOTE CHRONIC PAIN

IL-1β is a major proinflammatory cytokine and upregulated in the spinal cord under different chronic pain conditions.35, 62, 106 Specifically, several studies have shown IL-1β upregulation in astrocytes after bone cancer,41 nerve injury,33 hindpaw inflammation53, 107 and masseter inflammation.32 IL-1β was also found in neurons in the spinal cord.108, 109 Several lines of evidence support an important role of IL-1β for pain sensitization. Inhibition of spinal IL-1β signaling with intrathecal IL-1 receptor antagonist (IL-1ra) or neutralizing antibody has been shown to alleviate inflammatory, neuropathic, and cancer pain.32, 33, 62, 106, 107, 110, 111 Neuropathic pain is also markedly reduced in mouse strains with deletion of the IL-1 receptor type I or transgenic over-expression of IL-1ra.112 Conversely, intrathecal injection of IL-1β is sufficient to elicit pain hypersensitivity.113117

IL-1β released from astrocytes could directly modulate neuronal activity. Immunostaining shows that IL-1 receptor colocalizes with the NMDA receptor NR1 subunits in neurons of the spinal cord,107 trigeminal nucleus,32 and rostral ventromedial medulla.33 In primary cultured neurons, IL-1β regulates the phosphorylation of the NMDAR NR2B and NR1 subunit.32, 118 IL-1β-mediated enhancement of NR1 subunit phosphorylation in the spinal cord may facilitate inflammatory pain and bone cancer pain.107, 119 In particular, our ex vivo electrophysiological study using patch clamp recordings in lamina II neurons demonstrated that bath application of IL-1β onto isolated spinal cord slices can markedly enhance NMDA-induced current.106 Perfusion of spinal slices with IL-1β also increases the frequency and amplitude of spontaneous postsynaptic currents (sEPSCs) in dorsal horn neurons, indicating that IL-1β can directly enhance excitatory synaptic transmission.106 While the frequency increase of sEPSCs results from increased glutamate release from presynaptic terminals, the amplitude increase is caused by enhanced signaling of glutamate receptor (AMPA-subtype) in postsynaptic sites. IL-1β also increases the excitability of nociceptors via IL-1R that is expressed in small size primary sensory neurons,120 leading to increased glutamate release in nociceptor central terminals in the spinal cord. Strikingly, IL-1β can further modulate inhibitory synaptic transmission in dorsal horn neurons. Bath application of IL-1β reduces the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and inhibits GABA-and glycine-induced currents in lamina II neurons,106 which will contribute to disinhibition (loss of inhibition), an important mechanism that is increasingly appreciated for the generation of neuropathic pain.121, 122 Collectively, these studies suggest that IL-1β powerfully modulates synaptic transmission by a) enhancing excitatory synaptic transmission and b) reducing inhibitory synaptic transmission. In addition, IL-1β also produces long-term neuronal plasticity in the pain circuit by inducing the phosphorylation of the transcription factor CREB9, 106 and expression of COX-2 in spinal cord neurons.123

IL-1β is synthesized as a precursor and requires a protease for its activation via cleavage to produce biological function. Notably, caspase-1 is not the only enzyme for IL-1β cleavage.114 MMPs have been implicated in the cleavage of extracellular matrix proteins, cytokines, and chemokines to control inflammation and tissue remodeling associated with various neurodegenerative diseases.124127 Several studies showed that MMP-9 and MMP-2 are involved in IL-1β cleavage.114, 125, 128 Particularly, MMP2 is persistently induced in astrocytes after spinal nerve ligation.114 Treatment of MMP-2 siRNA in the late-phase of nerve injury blocks IL-1β cleavage in the spinal cord and reduces mechanical allodynia.114 These data suggest that astrocyte-derived MMP-2 may maintain neuropathic pain by active cleavage of IL-1β.

MCP-1 (also called CCL2) is the chemokine that is highly produced by astrocytes. MCP-1 expression is increased in spinal cord astrocytes after spinal nerve ligation52 and spinal cord contusion injuries.105 Several studies demonstrate that activated astrocytes in vitro also produce MCP-1.52, 129132 MCP-1 was found in astrocytes in the brain after demyelinating lesions,133, 134 mechanical injury,135 entorhinodentate axon transaction,136 and focal cerebral ischemia.137

CCR2, the major receptor of MCP-1, is expressed in DRG neurons and increased in these neurons after nerve injury.138 CCR2 is also constitutively expressed in spinal cord neurons,52, 139 which is upregulated after nerve injury.52 Our recent study indicated a direct action of MCP-1 on spinal cord neurons. In isolated spinal cord slices, perfusion of MCP-1 immediately increases the frequencies of sEPSCs and the amplitude in lamina II neurons of the dorsal horn.52 MCP-1 also rapidly (< 2 min) enhances NMDA- and AMPA-induced inward currents.52, indicating a potentiation of glutamatergic synaptic transmission, which has been strongly implicated in central sensitization and hyperalgesia,9, 122 Additionally, Gosselin et al.139 demonstrated in neonatal cultures that MCP-1 inhibits GABA-induced currents in spinal neurons without affecting the electrical properties of these neurons. Thus, MCP-1 also modulates inhibitory synaptic transmission in spinal cord neurons.

In parallel with electrophysiological evidence, behavioral evidence shows that spinal injection of MCP-1 induces rapid heat hyperalgesia, starting at 15 min, peaking at 30 min, and recovering at 24 h.52 Moreover, incubation of spinal cord slice with MCP-1 induces a rapid (within 5 minutes) phosphorylation of the extracellular signal-regulated kinase (pERK) in superficial dorsal horn neurons52, which is regarded as a marker for spinal nociceptive neuron sensitization (central sensitization)140. Thus, the rapid phosphorylation of ERK in dorsal horn neurons by MCP-1 supports a direct action of MCP-1 on spinal cord neurons and its involvement in central sensitization. In neuropathic pain models, MCP-1 neutralizing antibody reduces mechanical allodynia induced by SNL52 or CCI.141 Nerve injury-evoked mechanical allodynia is also reduced by CCR2 antagonist or in mice lacking CCR2.142145 Taken together, these studies demonstrate an important role of MCP-1/CCR2 in chronic pain via astrocyte-neuron interaction (Fig. 3). In additional to a direct action of neurons, astrocyte-produced MCP-1 may also act on microglia to induce proliferation and migration of microglia in the spinal cord, which can further enhance pain.143

Figure 3
Schematic showing how astrocytes in the spinal cord enhance synaptic transmission and promote chronic pain

MAP KINASE SIGNALING IN ASTROCYTES ENHANCES CHRONIC PAIN

Mounting evidence has demonstrated important roles of mitogen-activated protein kinases (MAPKs)—ERK, p38, and JNK—in chronic pain sensitization.146 Of interest these MAPKs are differentially activated in spinal cord glial cells after nerve injury. While p38 is persistently activated in microglia at all the times examined,31, 147, 148 ERK is only activated in microglia in the early-phase (first several days) of nerve injury.100 In the late-phase (>3 weeks) of nerve injury, pERK is induced in spinal astrocytes.42, 100 Spinal inhibition of this late-phase activation of ERK by intrathecal administration of a MEK inhibitor reverses mechanical allodynia, implicating a role of astrocytic ERK in the maintenance of neuropathic pain.100 Intraplantar injection of CFA also induces pERK in spinal cord astrocytes in the late-phase of this inflammatory pain condition.149

We will focus our discussion on JNK, also called stress-activated protein kinase, which is well known for its role in regulating apoptosis and neurodegeneration.140 But JNK activation in spinal astrocytes after peripheral nerve injury is not associated with apoptosis in astrocytes.31 Rather, JNK activation in astrocytes regulates the expression and release of chemokines.52 SNL induces a persistent (> 3 weeks) increase of phosphorylated JNK (pJNK) in the spinal cord, particularly in reactive astrocytes.31 Increase in pJNK was also found in spinal astrocytes in other neuropathic conditions such as partial sciatic nerve injury42 and amyotrophic lateral sclerosis.150 pJNK is further induced in spinal cord astrocytes in inflammatory pain conditions following intraplantar injection of carrageenan55 and CFA56. In particular, CFA elicits a bilateral phosphorylation of JNK, starting at 6 hours and maintaining after 2 weeks.56 Despite there are three isoforms of JNK (JNK1, JNK2 and JNK3), JNK1 is the isoform that is expressed in spinal astrocytes and hyperphosphorylated after SNL and CFA injection.31, 56 In parallel, inflammatory pain is reduced in mice lacking JNK1 but not JNK2.56

The role of astrocyte JNK in pain control has been also evaluated by intrathecal injection of the JNK inhibitor SP600125. Administration of SP600125, either before or after nerve injury, can both attenuate neuropathic pain after SNL.31, 151 SP600125 also suppresses neuropathic pain in a diabetes model of neuropathic pain.152 The peptide inhibitor D-JNKI-1 is a more potent and selective inhibitor of JNK. A single bolus injection of D-JNKI-1 can block SNL-induced mechanical allodynia for more than 6 hours.31

How does JNK signaling in astrocytes control chronic pain? JNK activation in astrocytes results in the production of various inflammatory mediators. In cultured astrocytes there is a JNK-dependent expression of COX-2 and iNOS as well as the release of NO, PGE2 and IL-6.153 Notably, stimulation of astrocytes with TNF-α not only activates JNK but also induces a marked upregulation of several chemokines, such as MCP-1, KC, IP-10.52 Strikingly, TNF-α induces a substantial increase (>100 fold), both in the expression and release of MCP-1 in astrocyte cultures; and this increase is completely blocked by JNK inhibition.52 JNK activation in astrocytes also leads to the production of MCP-1 in vivo.52 Thus, JNK activation in astrocytes can enhance pain via producing chemokines such as MCP-1, which is known to increase the sensitivity of dorsal horn neurons.154

JNK is activated by the transforming growth factor (TGF)-activated kinase 1 (TAK1), a member of the MAPK kinase kinase family. Interestingly, peripheral nerve injury induces TAK1 upregulation in hyperactive astrocytes in the spinal cord.155 Intrathecal administration of TAK1 antisense oligodeoxynucleotides, either before and after nerve injury, can reduce nerve injury-induced mechanical allodynia.155

Basic fibroblast factor (bFGF) is a well-known activator of astrocytes and induces mitosis, growth, differentiation, and gliosis of astrocytes.156, 157 Spinal nerve ligation induces a substantial increase of bFGF in reactive astrocytes in the late phase (3 weeks after injury, Fig. 2). Intrathecal infusion of bFGF induces persistent JNK phosphorylation and GFAP expression in the spinal cord, which is associated with the development of mechanical allodynia.22 Conversely, intrathecal injection of a bFGF neutralizing antibody can reverse nerve injury-induced mechanical allodynia.102 Compared to a transient JNK activation by TNF-α, bFGF induces a sustained activation of JNK in astrocyte cultures.22, 52 Therefore, bFGF, produced in astrocytes in the late-phase of injury, may maintain chronic pain via sustained JNK activation in astrocytes.

CONCLUSIONS AND CLINICAL IMPLICATIONS

In summary, we have reviewed behavioral, histochemical, and electrophysiological evidence to support a rising role of astrocytes in chronic pain sensitization. We also demonstrate how astrocytes promote chronic pain via neuronal-glial interactions (Fig. 3). After peripheral nerve injury or tissue damage in the skin, muscle, or joint (e.g., arthritis), astrocytes are activated in the spinal cord, in response to neurotransmitters/neuromodulators (e.g., ATP, glutamate, neuropeptides) and inflammatory mediators (e.g., TNF-α) released after injuries. Astrocyte activation may manifest as the activation of several intracellular signaling pathways such as the JNK and ERK pathways or/and up-regulation of GFAP and astrogliosis/hypertrophy (Fig. 3a). Activation of the JNK or/and ERK results in the production of proinflammatory cytokines and chemokines (e.g., IL-1β and MCP-1). These mediators can act at both presynaptic sites on primary afferents and post-synaptic sites on dorsal horn neurons to increase excitation and decrease inhibition of spinal cord nociceptive neurons, leading to enhanced pain states (Fig. 3b).

Given the important role of astrocytes in chronic pain facilitation, targeting astrocytes could reveal novel therapies for the management of chronic pain. However, caution must be taken when we consider strategies to target astrocytes, since astrocytes play an essential supportive and protective role in the CNS.158 Inhibition of reactive astrocytes with the toxin fluorocitrate has been shown to retard neurovascular remodeling and recovery after focal cerebral ischemia.159 Thus, it is important to target specific signaling events in astroctyes, without disrupting the overall well being of astrocytes. As discussed in Table-1, all the signaling molecules that are induced in astrocytes under chronic pain conditions and contribute to pain behaviors can be potentially targeted. In particular, JNK inhibitor not only exhibits anti-allodynic action but also has a neuroprotecitve role.160 JNK inhibitor further reduces tumor growth36 and insulin resistance161, 162, therefore, should be beneficial in pain conditions associated with cancer and diabetic neuropathy.

Finally, it is worthy to note that all the evidence we present is from animal studies. Indeed, astrocytes from human are quite different.163 The human brain appears to contain subtypes of GFAP-positive astrocytes that are not represented in rodents. Strikingly, in human cortex, astrocytes are >2 fold larger in diameter and extend 10-fold more GFAP-positive primary processes than their rodent counterparts. The domain of a single human astrocyte has been estimated to contain up 2 million synapses.164 Hence, it is reasonable to postulate human astrocytes may play a more important role in chronic pain control than rodent astrocytes.

Acknowledgements

This work was supported by NIH R01 grants NS54932, NS67686, and DE17794.

REFERENCES

1. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203–210. [PubMed]
2. Lundeberg T, Ekholm J. Pain--from periphery to brain. Disabil Rehabil. 2002;24:402–406. [PubMed]
3. Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66:355–474. [PubMed]
4. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959–1964. [PubMed]
5. Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci. 1992;15:96–103. [PubMed]
6. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mechanisms of cancer pain. Nat Rev Cancer. 2002;2:201–209. [PubMed]
7. Willis CL, Davis TP. Chronic inflammatory pain and the neurovascular unit: a central role for glia in maintaining BBB integrity? Curr Pharm Des. 2008;14:1625–1643. [PubMed]
8. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32. [PMC free article] [PubMed]
9. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705. [PubMed]
10. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284. [PMC free article] [PubMed]
11. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524–1534. [PubMed]
12. Ho KY, Siau C. Chronic pain management: therapy, drugs and needles. Ann Acad Med Singapore. 2009;38:929–930. [PubMed]
13. Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev. 2006;51:240–264. [PubMed]
14. Aldskogius H, Kozlova EN. Central neuron-glial and glial-glial interactions following axon injury. Prog Neurobiol. 1998;55:1–26. [PubMed]
15. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–1318. [PubMed]
16. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–1386. [PubMed]
17. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–1394. [PubMed]
18. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–1368. [PubMed]
19. McMahon SB, Malcangio M. Current challenges in glia-pain biology. Neuron. 2009;64:46–54. [PubMed]
20. Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol. 2008;21:570–579. [PMC free article] [PubMed]
21. Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol (Oxf) 2006;187:321–327. [PubMed]
22. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006;2:259–269. [PMC free article] [PubMed]
23. Suter MR, Wen YR, Decosterd I, Ji RR. Do glial cells control pain? Neuron Glia Biol. 2007;3:255–268. [PMC free article] [PubMed]
24. Watkins LR, Hutchinson MR, Ledeboer A, et al. Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun. 2007;21:131–146. [PMC free article] [PubMed]
25. Romero-Sandoval EA, Horvath RJ, DeLeo JA. Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs. 2008;9:726–734. [PMC free article] [PubMed]
26. Hald A. Spinal astrogliosis in pain models: cause and effects. Cell Mol Neurobiol. 2009;29:609–619. [PubMed]
27. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10:23–36. [PMC free article] [PubMed]
28. Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27:6473–6477. [PubMed]
29. Garrison CJ, Dougherty PM, Kajander KC, Carlton SM. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 1991;565:1–7. [PubMed]
30. Colburn RW, Rickman AJ, DeLeo JA. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol. 1999;157:289–304. [PubMed]
31. Zhuang ZY, Wen YR, Zhang DR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci. 2006;26:3551–3560. [PubMed]
32. Guo W, Wang H, Watanabe M, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007;27:6006–6018. [PMC free article] [PubMed]
33. Wei F, Guo W, Zou S, Ren K, Dubner R. Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci. 2008;28:10482–10495. [PMC free article] [PubMed]
34. Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci. 2004;20:467–473. [PubMed]
35. Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA. Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res. 1999;829:209–221. [PubMed]
36. Gao YJ, Cheng JK, Zeng Q, et al. Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol. 2009;219:146–155. [PMC free article] [PubMed]
37. Fujita M, Andoh T, Ohashi K, et al. Roles of kinin B(1) and B(2) receptors in skin cancer pain produced by orthotopic melanoma inoculation in mice. Eur J Pain. 2009 [PubMed]
38. Zhang HW, Iida Y, Andoh T, et al. Mechanical hypersensitivity and alterations in cutaneous nerve fibers in a mouse model of skin cancer pain. J Pharmacol Sci. 2003;91:167–170. [PubMed]
39. Schwei MJ, Honore P, Rogers SD, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci. 1999;19:10886–10897. [PubMed]
40. Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain. 2009;13:138–145. [PubMed]
41. Zhang RX, Liu B, Wang L, et al. Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain. 2005;118:125–136. [PubMed]
42. Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain. 2002;99:175–184. [PubMed]
43. Zhang J, De Koninck Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem. 2006;97:772–783. [PubMed]
44. Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int. 2004;45:397–407. [PubMed]
45. Cavaliere C, Cirillo G, Rosaria Bianco M, et al. Gliosis alters expression and uptake of spinal glial amino acid transporters in a mouse neuropathic pain model. Neuron Glia Biol. 2007;3:141–153. [PubMed]
46. Svensson M, Eriksson NP, Aldskogius H. Evidence for activation of astrocytes via reactive microglial cells following hypoglossal nerve transection. J Neurosci Res. 1993;35:373–381. [PubMed]
47. Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci. 2008;28:12775–12787. [PubMed]
48. Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol. 1994;129:237–243. [PubMed]
49. Chen JJ, Lue JH, Lin LH, et al. Effects of pre-emptive drug treatment on astrocyte activation in the cuneate nucleus following rat median nerve injury. Pain. 2009 [PubMed]
50. Colburn RW, DeLeo JA, Rickman AJ, et al. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol. 1997;79:163–175. [PubMed]
51. Kim DS, Figueroa KW, Li KW, et al. Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected] Pain. 2009;143:114–122. [PMC free article] [PubMed]
52. Gao YJ, Zhang L, Samad OA, et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009;29:4096–4108. [PMC free article] [PubMed]
53. Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ, Inturrisi CE. N-Methyl-daspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain. 2009 [PMC free article] [PubMed]
54. Svensson CI, Brodin E. Spinal astrocytes in pain processing: non-neuronal cells as therapeutic targets. Mol Interv. 2010;10:25–38. [PubMed]
55. Svensson CI, Zattoni M, Serhan CN. Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med. 2007;204:245–252. [PMC free article] [PubMed]
56. Gao YJ, Xu ZZ, Liu YC, et al. The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain. 2010;148:309–319. [PMC free article] [PubMed]
57. Hofstetter CP, Holmstrom NA, Lilja JA, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8:346–353. [PubMed]
58. Davies JE, Proschel C, Zhang N, et al. Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol. 2008;7:24. [PMC free article] [PubMed]
59. Gao YJ, Ji RR. Neuroscience Meeting Planner. Society for Neuroscience; Chicago, IL: 2009. Intrathecal injection of activated astrocytes induces tactile allodynia by producing MCP-1. Program No. 561.17. 2009. Online.
60. Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology. 1994;33:1471–1478. [PubMed]
61. Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain. 1997;71:225–235. [PubMed]
62. Milligan ED, Twining C, Chacur M, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–1040. [PubMed]
63. Obata H, Eisenach JC, Hussain H, Bynum T, Vincler M. Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain. 2006;7:816–822. [PubMed]
64. Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain. 2007;11:223–230. [PubMed]
65. Okada-Ogawa A, Suzuki I, Sessle BJ, et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci. 2009;29:11161–11171. [PMC free article] [PubMed]
66. Ledeboer A, Mahoney JH, Milligan ED, et al. Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats. J Pain. 2006;7:757–767. [PubMed]
67. Huck S, Grass F, Hortnagl H. The glutamate analogue alpha-aminoadipic acid is taken up by astrocytes before exerting its gliotoxic effect in vitro. J Neurosci. 1984;4:2650–2657. [PubMed]
68. Khurgel M, Koo AC, Ivy GO. Selective ablation of astrocytes by intracerebral injections of alpha-aminoadipate. Glia. 1996;16:351–358. [PubMed]
69. Rodriguez MJ, Martinez-Sanchez M, Bernal F, Mahy N. Heterogeneity between hippocampal and septal astroglia as a contributing factor to differential in vivo AMPA excitotoxicity. J Neurosci Res. 2004;77:344–353. [PubMed]
70. Wang W, Wang W, Mei X, et al. Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One. 2009;4:e6973. [PMC free article] [PubMed]
71. Beart PM, O'Shea RD. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol. 2007;150:5–17. [PMC free article] [PubMed]
72. Huang YH, Bergles DE. Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol. 2004;14:346–352. [PubMed]
73. Tawfik VL, Lacroix-Fralish ML, Bercury KK, et al. Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. Glia. 2006;54:193–203. [PubMed]
74. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675–686. [PubMed]
75. Tanaka K, Watase K, Manabe T, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:1699–1702. [PubMed]
76. Katagiri H, Tanaka K, Manabe T. Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci. 2001;14:547–553. [PubMed]
77. Levenson J, Weeber E, Selcher JC, et al. Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci. 2002;5:155–161. [PubMed]
78. Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci. 2003;23:2899–2910. [PubMed]
79. Wang W, Wang W, Wang Y, et al. Temporal changes of astrocyte activation and glutamate transporter-1 expression in the spinal cord after spinal nerve ligation-induced neuropathic pain. Anat Rec (Hoboken) 2008;291:513–518. [PubMed]
80. Xin WJ, Weng HR, Dougherty PM. Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol Pain. 2009;5:15. [PMC free article] [PubMed]
81. Tawfik VL, Regan MR, Haenggeli C, et al. Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience. 2008;152:1086–1092. [PMC free article] [PubMed]
82. Liaw WJ, Stephens RL, Jr., Binns BC, et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain. 2005;115:60–70. [PubMed]
83. Weng HR, Chen JH, Cata JP. Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience. 2006;138:1351–1360. [PubMed]
84. Maeda S, Kawamoto A, Yatani Y, et al. Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain. 2008;4:65. [PMC free article] [PubMed]
85. Chiang CY, Wang J, Xie YF, et al. Astroglial glutamate-glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J Neurosci. 2007;27:9068–9076. [PubMed]
86. Kozai T, Yamanaka H, Dai Y, et al. Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury. Glia. 2007;55:595–603. [PubMed]
87. Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci U S A. 2006;103:6735–6740. [PMC free article] [PubMed]
88. Pang PT, Teng HK, Zaitsev E, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487–491. [PubMed]
89. Hoffman KB, Martinez J, Lynch G. Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation? Brain Res. 1998;811:29–33. [PubMed]
90. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature. 1993;361:453–457. [PubMed]
91. Blomstrand F, Khatibi S, Muyderman H, et al. 5-Hydroxytryptamine and glutamate modulate velocity and extent of intercellular calcium signalling in hippocampal astroglial cells in primary cultures. Neuroscience. 1999;88:1241–1253. [PubMed]
92. Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci. 2001;2:185–193. [PubMed]
93. Giaume C, McCarthy KD. Control of gap-junctional communication in astrocytic networks. Trends Neurosci. 1996;19:319–325. [PubMed]
94. Nagy JI, Dudek FE, Rash JE. Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev. 2004;47:191–215. [PubMed]
95. Rohlmann A, Laskawi R, Hofer A, et al. Facial nerve lesions lead to increased immunostaining of the astrocytic gap junction protein (connexin 43) in the corresponding facial nucleus of rats. Neurosci Lett. 1993;154:206–208. [PubMed]
96. Lee IH, Lindqvist E, Kiehn O, Widenfalk J, Olson L. Glial and neuronal connexin expression patterns in the rat spinal cord during development and following injury. J Comp Neurol. 2005;489:1–10. [PubMed]
97. Qin M, Wang JJ, Cao R, et al. The lumbar spinal cord glial cells actively modulate subcutaneous formalin induced hyperalgesia in the rat. Neurosci Res. 2006;55:442–450. [PubMed]
98. Spataro LE, Sloane EM, Milligan ED, et al. Spinal gap junctions: potential involvement in pain facilitation. J Pain. 2004;5:392–405. [PubMed]
99. Lan L, Yuan H, Duan L, et al. Blocking the glial function suppresses subcutaneous formalin-induced nociceptive behavior in the rat. Neurosci Res. 2007;57:112–119. [PubMed]
100. Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain. 2005;114:149–159. [PubMed]
101. Peters CM, Rogers SD, Pomonis JD, et al. Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis. Exp Neurol. 2003;180:1–13. [PubMed]
102. Madiai F, Goettl VM, Hussain SR, et al. Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain. J Mol Neurosci. 2005;27:315–324. [PubMed]
103. Madiai F, Hussain SR, Goettl VM, et al. Upregulation of FGF-2 in reactive spinal cord astrocytes following unilateral lumbar spinal nerve ligation. Exp Brain Res. 2003;148:366–376. [PubMed]
104. Garry EM, Delaney A, Blackburn-Munro G, et al. Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci. 2005;30:523–537. [PubMed]
105. Knerlich-Lukoschus F, Juraschek M, Blomer U, et al. Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat. J Neurotrauma. 2008;25:427–448. [PubMed]
106. Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008;28:5189–5194. [PMC free article] [PubMed]
107. Zhang RX, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008;135:232–239. [PMC free article] [PubMed]
108. DeLeo JA, Colburn RW, Rickman AJ. Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res. 1997;759:50–57. [PubMed]
109. Fu D, Guo Q, Ai Y, et al. Glial activation and segmental upregulation of interleukin-1beta (IL-1beta) in the rat spinal cord after surgical incision. Neurochem Res. 2006;31:333–340. [PubMed]
110. Milligan ED, O'Connor KA, Nguyen KT, et al. Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci. 2001;21:2808–2819. [PubMed]
111. Sweitzer S, Martin D, DeLeo JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience. 2001;103:529–539. [PubMed]
112. Wolf G, Gabay E, Tal M, Yirmiya R, Shavit Y. Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain. 2006;120:315–324. [PubMed]
113. Ji GC, Zhang YQ, Ma F, Wu GC. Increase of nociceptive threshold induced by intrathecal injection of interleukin-1beta in normal and carrageenan inflammatory rat. Cytokine. 2002;19:31–36. [PubMed]
114. Kawasaki Y, Xu ZZ, Wang X, et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med. 2008;14:331–336. [PMC free article] [PubMed]
115. Tadano T, Namioka M, Nakagawasai O, et al. Induction of nociceptive responses by intrathecal injection of interleukin-1 in mice. Life Sci. 1999;65:255–261. [PubMed]
116. Sung CS, Wen ZH, Chang WK, et al. Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res. 2004;1015:145–153. [PubMed]
117. Reeve AJ, Patel S, Fox A, Walker K, Urban L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain. 2000;4:247–257. [PubMed]
118. Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E. Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones. Br J Pharmacol. 2008;153:775–783. [PMC free article] [PubMed]
119. Zhang RX, Liu B, Li A, et al. Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. Neuroscience. 2008;154:1533–1538. [PMC free article] [PubMed]
120. Binshtok AM, Wang H, Zimmermann K, et al. Nociceptors are interleukin-1beta sensors. J Neurosci. 2008;28:14062–14073. [PMC free article] [PubMed]
121. Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017–1021. [PubMed]
122. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. [PubMed]
123. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471–475. [PubMed]
124. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39:279–291. [PubMed]
125. Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4:617–629. [PubMed]
126. Yong VW. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci. 2005;6:931–944. [PubMed]
127. Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008;19:34–41. [PMC free article] [PubMed]
128. Schonbeck U, Mach F, Libby P. Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol. 1998;161:3340–3346. [PubMed]
129. Croitoru-Lamoury J, Guillemin GJ, Boussin FD, et al. Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia. 2003;41:354–370. [PubMed]
130. Meeuwsen S, Persoon-Deen C, Bsibsi M, Ravid R, van Noort JM. Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia. 2003;43:243–253. [PubMed]
131. El-Hage N, Gurwell JA, Singh IN, et al. Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia. 2005;50:91–106. [PubMed]
132. Mojsilovic-Petrovic J, Callaghan D, Cui H, et al. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J Neuroinflammation. 2007;4:12. [PMC free article] [PubMed]
133. Van Der Voorn P, Tekstra J, Beelen RH, et al. Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. Am J Pathol. 1999;154:45–51. [PMC free article] [PubMed]
134. Tanuma N, Sakuma H, Sasaki A, Matsumoto Y. Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol. 2006;112:195–204. [PubMed]
135. Huang D, Han Y, Rani MR, et al. Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation. Immunol Rev. 2000;177:52–67. [PubMed]
136. Babcock AA, Kuziel WA, Rivest S, Owens T. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci. 2003;23:7922–7930. [PubMed]
137. Yan YP, Sailor KA, Lang BT, et al. Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27:1213–1224. [PubMed]
138. White FA, Sun J, Waters SM, et al. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A. 2005;102:14092–14097. [PMC free article] [PubMed]
139. Gosselin RD, Varela C, Banisadr G, et al. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J Neurochem. 2005;95:1023–1034. [PubMed]
140. Gao YJ, Ji RR. c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J. 2009;2:11–17. [PMC free article] [PubMed]
141. Thacker MA, Clark AK, Bishop T, et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain. 2009;13:263–272. [PubMed]
142. Abbadie C, Lindia JA, Cumiskey AM, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A. 2003;100:7947–7952. [PMC free article] [PubMed]
143. Zhang J, Shi XQ, Echeverry S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci. 2007;27:12396–12406. [PubMed]
144. Bhangoo S, Ren D, Miller RJ, et al. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain. 2007;3:38. [PMC free article] [PubMed]
145. Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol Pain. 2009;5:48. [PMC free article] [PubMed]
146. Ji RR, Gereau RWt, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60:135–148. [PMC free article] [PubMed]
147. Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017–4022. [PubMed]
148. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia. 2004;45:89–95. [PubMed]
149. Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ, Inturrisi CE. N-Methyl-daspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain. 2010;148:237–246. [PMC free article] [PubMed]
150. Migheli A, Piva R, Atzori C, Troost D, Schiffer D. c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1997;56:1314–1322. [PubMed]
151. Obata K, Yamanaka H, Kobayashi K, et al. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci. 2004;24:10211–10222. [PubMed]
152. Daulhac L, Mallet C, Courteix C, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol. 2006;70:1246–1254. [PubMed]
153. Falsig J, Porzgen P, Lotharius J, Leist M. Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. J Immunol. 2004;173:2762–2770. [PubMed]
154. Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126:56–68. [PMC free article] [PubMed]
155. Katsura H, Obata K, Miyoshi K, et al. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia. 2008;56:723–733. [PubMed]
156. Ferrara N, Ousley F, Gospodarowicz D. Bovine brain astrocytes express basic fibroblast growth factor, a neurotropic and angiogenic mitogen. Brain Res. 1988;462:223–232. [PubMed]
157. Eclancher F, Perraud F, Faltin J, Labourdette G, Sensenbrenner M. Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain. Glia. 1990;3:502–509. [PubMed]
158. Takano T, Oberheim N, Cotrina ML, Nedergaard M. Astrocytes and ischemic injury. Stroke. 2009;40:S8–12. [PMC free article] [PubMed]
159. Hayakawa K, Nakano T, Irie K, et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2009 [PMC free article] [PubMed]
160. Borsello T, Clarke PG, Hirt L, et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med. 2003;9:1180–1186. [PubMed]
161. Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes. Horm Metab Res. 2009;41:523–530. [PubMed]
162. Ijaz A, Tejada T, Catanuto P, et al. Inhibition of C-jun N-terminal kinase improves insulin sensitivity but worsens albuminuria in experimental diabetes. Kidney Int. 2009;75:381–388. [PubMed]
163. Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276–3287. [PMC free article] [PubMed]
164. Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 2006;29:547–553. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...