Contribution of macrophages to peripheral neuropathic pain pathogenesis

Life Sciences 93 (2013) 870–881

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Minireview

Contribution of macrophages to peripheral neuropathic pain pathogenesis Violeta Ristoiu ⁎ Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independenţei 91-95, 050095 Bucharest, Romania

a r t i c l e

i n f o

Article history: Received 13 July 2013 Accepted 5 October 2013 Keywords: Macrophages Microglia Peripheral neuropathic pain

a b s t r a c t Neuropathic pain pathogenesis is not only confined to changes in the activity of neuronal systems, but also involves neuro-immune interactions mediated by inflammatory cytokines and chemokines. Among the immune cells involved in these interactions, macrophages and their central nervous system counterparts – microglia – are actively involved in the generation of peripheral neuropathic pain. Depending on the type of lesion (traumatic, metabolic, neurotoxic, infections or tumor invasion), the profile of the activated macrophages and microglia in terms of time, place and subtype can substantially vary, due to their remarkable plasticity that allows tuning their physiology according to microenvironmental signals. Knowing what and when specific macrophages activate after a peripheral nerve lesion could help in creating a pattern that can be further used to target the macrophages with cell-specific therapeutics and remit chronicization and complications of neuropathic pain. This minireview summarizes recent findings on the specific contribution of macrophages in different neuropathic pain models. © 2013 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traumatic-induced neuropathic pain models . . . . . . . . . . . . . . . Contribution of hematogenous macrophages . . . . . . . . . . . . . Contribution of resident macrophages and microglia . . . . . . . . . Specific kinases activated in traumatic-induced neuropathic pain models Metabolic-induced neuropathic pain model . . . . . . . . . . . . . . . Diabetic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . Neurotoxic-induced neuropathic pain models . . . . . . . . . . . . . . Acrylamide-induced neuropathy . . . . . . . . . . . . . . . . . . Cancer chemotherapy-induced peripheral neuropathy (CIPN) . . . . . Infection-induced neuropathic pain models . . . . . . . . . . . . . . . HIV-1 gp120 induced neuropathy . . . . . . . . . . . . . . . . . . Post-herpetic neuralgia . . . . . . . . . . . . . . . . . . . . . . . Tumor invasion-induced neuropathic pain models . . . . . . . . . . . . Cancer-induced bone pain . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction ⁎ Splaiul Independenţei 91-95, 050095 Bucharest, Romania. Tel.: + 40 21 3181573(office); fax: + 40 21 3181573. E-mail address: [email protected]. 0024-3205/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2013.10.005

Neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction in the peripheral or central nervous system. Peripheral neuropathic pain results from traumatic or metabolic injury, neurotoxic

V. Ristoiu / Life Sciences 93 (2013) 870–881

axonal regrowth as well (Moalem and Tracey, 2006; Webber and Zochodne, 2010). In parallel to these processes at nerve level, there is an activation of the resident macrophages together with an increased infiltration of the hematogenous macrophages in the dorsal root ganglia (DRG), but their role is poorly understood. These degeneration and subsequent regeneration processes at the injured peripheral nerves are frequently associated with neuropathic pain development. It is not yet clear if the cellular and molecular changes involved in Wallerian degeneration are simultaneously involved in the induction and maintenance of neuropathic pain, but many experimental data support macrophage implication in pain processes following peripheral nerve injury. Depletion of hematogenous macrophages with liposome-encapsulated clodronate leads to a reduction of hyperalgesia and allodynia after traumatic or metabolic nerve injury (Liu et al., 2000; Mert et al., 2009). Minocycline reverses the activation of macrophages by retarding their migration to the nerve injury after chronic constriction injury (CCI) and spared nerve injury (SNI) (Ghanouni et al., 2012; Mika et al., 2010). The anti-inflammatory cytokine TGF-β1 delays the development of both thermal hyperalgesia and mechanical allodynia by reducing the number of cytokine/chemokine secreting MAC1(CD11b/CD18) (+) macrophages after partial sciatic nerve ligation (PSNL) (Echeverry et al., 2012). In Wlds (slow Wallerian degeneration) mice in which recruitment of macrophages to the site of injury is delayed, the development of thermal hyperalgesia is also prevented (Myers et al., 1996; Sommer and Schafers, 1998). Additionally, cytokines and chemokines secreted by macrophages, such as TNF-α (tumor necrosis factor-α), interleukins IL-1β, IL-6 and MIP-1α (macrophage inflammatory protein 1-α) are potential mediators of hyperalgesia through direct receptor-mediated actions on afferent fibers or indirect actions involving further mediators (Kawasaki et al., 2008;

chemicals, infection or tumor invasion (Woolf, 2004), while central neuropathic pain results from spinal cord injury, stroke or multiple sclerosis (Ducreux et al., 2006). Its pathogenesis is not only confined to changes in the activity of neuronal systems, but also involves interactions between neurons, immune cells and immune-like glial cells mediated by inflammatory cytokines and chemokines (Gosselin et al., 2010; Scholz and Woolf, 2007). Among the immune cells involved in these neuroimmune interactions, macrophages which are the primary sensors of danger in the host, might act as initiators of neuropathic pain. Macrophages are present in virtually all tissues and have a plastic, chameleon-like phenotype, changing easily their physiology in response to environmental stimuli. They originate from circulating peripheral blood monocytes, which either migrate into tissue to form tissue-specific resident macrophages (Gordon and Taylor, 2005), or remain in the blood to form an “inflammatory” population which infiltrate in the tissues on-demand, in response to inflammation (Mosser and Edwards, 2008). Macrophages act as house-keeping cells, removing through phagocytizing the worn-out cells or other debris, and as immune effector cells in both innate and adaptative immune responses (Mosser and Edwards, 2008). Injury to peripheral nerves triggers activation of resident macrophages and infiltration of hematogenous macrophages at the periphery, and activation of microglia at the central level. At the periphery, activated macrophages express specific surface markers, secrete cytokines/chemokines and mitogenic factors (Zhang and Mosser, 2008), and are involved in removing myelin debris as part of the Wallerian degeneration process — resident macrophages participate together with Schwann cells to an early phase, and the hematogenous macrophages participate during the late phase (Dubovy, 2011; Stoll et al., 1989). By rapid clearance of myelin debris macrophages facilitate

OX-42 OX-42 Iba-1

OX-42

OX-42 OX-42

OX-42

OX-42 Iba-1

Spinal cord

Iba-1 OX-42

Iba-1

ED-1

DRG

ED-1

Iba-1

MHC-II ED-1

Sciatic nerve 0

11

3

44

Days

ED-1

Iba-1 ED-1 ED-1 ED-1

ED-1 F4/80

F4/80

5

6

7

PSNL CCI SNI Ligation/transection Nerve crush SNL Lumbar disk herniation Trigeminal compression Diabetic NP Acrylamide-induced NP HIV-induced NP Chemotherapy-inducedNP Cancer bone pain Post-herpetic neuralgia

Iba-1

ED-1 ED-1

ED-1 OX-42 OX-42

2

ED-1

ED-1 F4/80

F4/80 ED-1

ED-1 Iba-1 ED-1

OX-42

ED-1

Iba-1 F4/80

F4/80

OX-42

Iba-1

Iba-1 Iba-1 ED-1 ED-1 MHC-II OX-42 ED-1 ED-2 Iba-1 MHC-II OX-42 ED-1

0

OX-42

OX-42 Iba-1

OX-42 OX-42 Iba-1 Iba-1 OX-42 OX-42 OX-42 Iba-1 Iba-1 OX-42 OX-42 Iba-1 Iba-1 ED-1 ED-1 F4/80

OX-42

871

18

29

ED-1

ED-1

3 10

4 12 5 11

6 13

7 14

8 15

9 10 17 11 18 12 16

Weeks

Fig. 1. The macrophage/microglia activation according to the pain model. Depending of the neuropathic pain model, the hematogenous and endogenous macrophages/microglia activate at different time points in sciatic nerve, dorsal root ganglia and spinal cord. The hematogenous macrophages express ED1/CD68, OX-42/Cd11b, F4/80 and MHC-II (major histocompatibility complex class II) markers, the resident macrophages express Iba-1 (ionized calcium binding adaptor molecule 1) and ED2/CD163 markers and microglia express OX-42/Cd11b and Iba-1. PSNL — partial sciatic nerve ligation, CCI — chronic constriction injury, SNI — spared nerve injury, SNL — spinal nerve ligation, NP — neuropathy.

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The purpose of the present review is to offer an overview of the current knowledge about the specific contribution of macrophages to injury-specific peripheral neuropathic pain pathogenesis. As both macrophages and microglia activate after a peripheral lesion and share a common origin (Rio-Hortega, 1932; Saijo and Glass, 2011), the time scale of activation, the cytokine/chemokine secretion and kinase up-regulation were summarized for both cell types at the peripheral nerves, DRG and spinal cord level in different neuropathic pain models. The cell subtypes were identified according to the markers they express as hematogenous macrophages (when expressing ED1/CD68, OX-42/ Cd11b, F4/80, MAC1 and MHC-II (major histocompatibility complex class II) markers), resident macrophages (when expressing Iba-1 (ionized calcium binding adaptor molecule 1) and ED2/CD163 markers) and microglia (when expressing OX-42/Cd11b and Iba-1). Fig. 1 offers an image at a glance of the macrophage/microglia activation according to the pain model, while below a more detailed analysis of their profile is made.

Lee and Zhang, 2012; Sommer and Kress, 2004). Nevertheless, some studies have shown that systemic depletion of macrophages has a limited effect on mechanical allodynia (Rutkowski et al., 2000). Microglia, the resident macrophages of central nervous system (CNS), play a very important pro-nociceptive role and act as initiators of neuropathic pain (Tsuda et al., 2005). In the healthy CNS microglia are not dormant, but perform immune surveillance, extending and retracting their ramified processes without overall cell displacement (Nimmerjahn et al., 2005). After an injury to the peripheral nervous system (PNS), microglia rapidly activate: their cell body increases in size, proximal processes become thicker, distal branches are less ramified, specific membrane ruffles develop, and the cells move to the damaged site where they show increased phagocytic activity and release of pro-inflammatory mediators (Hanisch and Kettenmann, 2007; Saijo and Glass, 2011). The activation of microglia was frequently associated with increased levels of MAP (mitogen-activated protein) kinases, such as p-p38 (phospho-p38) (Jin et al., 2003), p-ERK1/2 (Cheng et al., 2003), p-ERK5 (phospho-Extracellular Signal-Regulated Kinase) (Obata et al., 2007) and p-JNK (phospho-c-Jun N-terminal kinase) (Scholz et al., 2008), and increased cytokine secretion (Hatashita et al., 2008; Miyoshi et al., 2008). Preventing microglia activation with inhibitors of MAP kinases ERK1/2 and p-38 (Sweitzer et al., 2004; Tsuda et al., 2008), with gabapentin (Wodarski et al., 2009), minocycline (Lin et al., 2007; Pabreja et al., 2011) or lidocaine (Suzuki et al., 2011), proved to be an effective analgesic strategy.

Traumatic-induced neuropathic pain models Contribution of hematogenous macrophages It is widely believed that macrophages involved in the pathogenesis of neuropathies are of hematogenous origin, so many studies have

Table 1.1 Immune profile of peripheral nervous system in traumatic-induced neuropathic pain models. Pain model

Parameter

Macrophages/ microglia

Sciatic nerve Days Weeks F4/80 F4/80 (1, 7) (2) ED-1 OX-42 (3-4) (2, 4) ED-1 (4)

Hours

DRG Days F4/80 (mostly BN) L3-L5 (3) Iba-1 L4-L5 (2)

Weeks F4/80 (mostly BN) L3-L5 (2)

Hours

Spinal cord Days Iba-1 ipsidorsal horn (3,7)

Weeks Iba-1 ipsidorsal horn (2)

p-ERK1/2 Schwann cells (1)

Kinases

TNF-α

All tissue (1, 7)

IL-β

All tissue. (1)

IL-6

All tissue (1, 7) Mac1(+) (4)

PSNL

Cyto kines/ chemo kines

Hours

IFN-γ

MIP-1α/ CCL3

MIP-1β/ CCL4 RANTES/ CCL5

L4-L6 All tissue (7)

ED-1 (2, 4)

All tissue (1) F4/80 Schwann cells (1) MAC1(+) (4)

L4-L6 All tissue (7)

All tissue (7)

All tissue (7)

References Kim and Moalem-Taylor, 2011 Saika et al., 2012 Echeverry et al., 2012 Liou et al., 2013 Kiguchi et al., 2010 Ma and Quirion, 2005 Ma and Quirion, 2006 Komori et al., 2011 Kiguchi et al., 2009

Maeda et al., 2008 Liou et al., 2013 All tissue (2)

Feng et al., 2009 Liou et al., 2013

All tissue (2)

Feng et al., 2009 Maeda et al., 2008 Ma and Quirion, 2006 Ma and Quirion, 2005 Liou et al., 2013 Echeverry et al., 2012 Liou et al., 2013 Echeverry et al., 2012 Kiguchi et al., 2009

F4/80 Schwann cells (1)

Saika et al., 2012

All tissue (2)

Liou et al., 2013

Note: The color code indicates the references associated with a particular tissue. The italic letters indicate a correspondence between a certain parameter and a specific reference. PSNL — partial sciatic nerve ligation. F4/80, OX-42/CD11b, ED1/CD68, Iba-1 (ionized binding adapter protein-1), Mac1 (Macrophage-1 antigen) — are specific macrophages/microglia markers. p-ERK1/2 — phospho-Extracellular Signal-Regulated Kinase. MIP-1α/CCL3 — macrophage inflammatory protein 1-α/Chemokine (C–C motif) ligand 3, MIP-1β/CCL4 — macrophage inflammatory protein 1-β/Chemokine (C–C motif) ligand 4, RANTES/CCL5 — Regulated on Activation, Normal T cell Expressed and Secreted/Chemokine (C–C motif) ligand 5. The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L4…L6 represent the ipsilateral DRG where the particular aspect was investigated. BN — distribution between neurons. (Echeverry et al., 2012; Feng et al., 2009; Kiguchi et al., 2009; Kiguchi et al., 2010; Kim and Moalem-Taylor, 2011; Komori et al., 2011; Liou et al., 2013; Ma and Quirion, 2005; Ma and Quirion, 2006; Maeda et al., 2008; Saika et al., 2012).

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on the pain model, only some cytokines/chemokines have been associated with hematogenous macrophages. In the sciatic nerve, TNF-α, IL-6, IL-15, IL-18 and MIF (macrophage migration inhibitory factor) cytokines together with MIP-1α/CCL3 (macrophage inflammatory protein 1-α/Chemokine (C-C motif) ligand 3) and MIP-1β/CCL4 (macrophage inflammatory protein 1-β/Chemokine (C-C motif) ligand 4) chemokines, were specifically associated with F4/80, ED-1/CD68 (+), OX-42/CD11b (+) and MAC1(+) macrophages after PSNL, CCI, SNI and sciatic nerve crush (Tables 1.1, 1.2 and 1.3). In the DRG, TNF-β, IL-1β and IL-18 cytokines and SDF-1/CXCL1 2 (stromal cell-derived factor-1)/ Chemokine (C-X-C motif) were associated only with ED-1/CD68 (+) macrophages after CCI, sciatic nerve transection, sciatic nerve crush, SNL and L5 DRG compression (Tables 1.2, 1.3, 1.4 and 1.5). The distribution around DRG neurons as perineuronal rings of OX-42/CD11b (+) cells after CCI (Hu et al., 2007), of MHC-II (+) cells after sciatic/spinal nerve transection (Hu and McLachlan, 2002) and of ED-1/CD68 (+) cells after sciatic nerve ligation/transection or ventral root transection (Dubovy et al., 2006, 2007) and SNL (Dubovy et al., 2006) could possibly help in creating a gap–junction-like connection with the

investigated their contribution. In the sciatic nerve, activation of F4/80, ED-1/CD68 (+) and OX-42/CD11b (+) macrophages was detected at different time points after PSNL, CCI and sciatic nerve crush (Tables 1.1, 1.2 and 1.3), but they didn't show a distinctive spatial distribution inside the nerve. In the DRG on the other hand, F4/80, MHC-II (+), ED-1/CD68 (+) and OX-42/CD11b (+) macrophages invaded the tissue and either remained scattered between neurons or they formed perineuronal rings around medium and large neurons after PSNL, CCI, sciatic nerve ligation/transection or ventral root transection, SNL, lumbar disk herniation and L5 DRG compression (Tables 1.1, 1.2, 1.3, 1.4 and 1.5). As described in the supplementary section, the markers used for cell subtype identification are proteins specific for macrophage functioning in other instances as well. Their expression in these studies was just a mean of identifying the subtypes and no correlation was made between them and a particular change in macrophage physiology due to neuropathic lesion. There are two ways the hematogenous macrophages could possibly exert their influence: through secreted cytokines/chemokines or through a gap–junction-like connection with the neurons. Depending

Table 1.2 Immune profile of peripheral nervous system in traumatic-induced neuropathic pain models. Pain model

Parameter

Hours

Sciatic nerve Days Weeks ED-1 (7)

Macrophages/ microglia

CCI of sciatic nerve, median nerve or infraorbital nerve

TNF-α

All tissue (6)

All tissue (1) ED-1 (1-5)

Hours

DRG Days MHC-II ED1 (mostly BN) OX-42 (mostly AN) L4-L5 (7)

Weeks ED1 L4-L5 (2)

Hours

Spinal cord Days OX-42 Iba-1 laminae I-IV of ipsidorsal horn and ventral horn (7)

Weeks OX-42 laminae IIV of ipsidorsal horn and ventral horn (10)

OX-42 spinal trigeminal nucleus (1)

OX-42 Cuneate nucleus (2) OX-42 spinal trigeminal nucleus (2)

All tissue (1-3)

Sacerdote et al., 2008 Shubayev and Mayers, 2002

Intrathecal dyalisate (2) Intrathecal dyalisate (2)

IL-1β Cyto kines/ chemo kines

IL-6 ED -1 ( 5)

IL-15

IB4 dorsal horn (5)

Iba-1 (mostly AN) L4-L5 (7)

Macrophages/ microglia

SNI

Kinases Cyto kines/ chemo kines

MIF

OX-42 (12)

Whitehead et al., 2010

Whitehead et al., 2010

Gomez-Nicola et al., 2008

Dubovy et al., 2010

ED-1 L4-L5 (2)

SDF-1

References Gomez-Nicola et al., 2008 Hu et al., 2007 Dubovy et al., 2010 Scholz et al., 2008 Lin et al., 2011 Mika et al., 2009 Latremoliere et al., 2008

OX-42 Iba-1 ipsidorsal horn (7)

Vega-Avelaira et al., 2009 Scholz et al., 2008

p-p38 ipsi-L5 dorsal horn (7)

Scholz et al., 2008

Alexander et al., 2012

Note: The color code indicates the references associated with a particular tissue. The italic letters indicate a correspondence between a certain parameter and a specific reference. CCI — chronic constriction injury; SNI — spared nerve injury. MHC-II (major histocompatibility complex-class II), OX-42/CD11b, ED1/CD68, Iba-1 (ionized binding adapter protein-1) — are specific macrophages/microglia markers. p-p38 (phospho-p38 kinase). SDF-1/CXCL12 — stromal cell-derived factor-1/Chemokine (C-X-C motif), MIF — macrophage migration inhibitory factor. The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L4…L6 represent the ipsilateral DRG where the particular aspect was investigated. BN — distribution between neurons. AN — ring-distribution around neurons, beneath satellite cells sheath (Alexander et al., 2012; Dubovy et al., 2010; Gomez-Nicola et al., 2008; Hu et al., 2007; Latremoliere et al., 2008; Lin et al., 2011; Mika et al., 2009; Sacerdote et al., 2008; Scholz et al., 2008; Shubayev and Myers, 2002; Vega-Avelaira et al., 2009; Whitehead et al., 2010).

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between neurons after PSNL, sciatic or spinal nerve transection and lumbar disk herniation (Tables 1.1, 1.3 and 1.5), or enlarge their cell bodies and dispose as satellite cells around neurons after SNI and SNL (Tables 1.2 and 1.4). Similar to hematogenous macrophages, the distribution around DRG neurons could possibly help in creating a gap– junction connection with the DRG neurons, but again this was never proved so far. For microglia the data are more abundant: an increased number with no specific pattern of Iba-1 (+) or OX-42 (+) microglia has been described in the ipsilateral dorsal horn of the rat and mice spinal cord at different time points after PSNL, sciatic nerve CCI, SNI, sciatic nerve ligation/transection or ventral root transection, L5 spinal nerve crush, SNL (Tables 1.1, 1.2, 1.3 and 1.4), trigeminal compression (Table 1.5) and CCI of median nerve or infraorbital nerve (Table 1.2). In contrast to hematogenous macrophages, less cytokines were associated with endoneurial macrophages and microglia. IL-15 and IL-18 were specifically associated with microglia after CCI and SNL (Tables 1.2 and 1.4), while TNF-α was located inside the Iba-1 (+) resident macrophages of the DRG after lumbar disk herniation (Table 1.5). Even though only some cytokines/chemokines were specifically associated with macrophage subtypes in some pain models, the data in the literature about their contribution to traumatic neuropathic pain pathogenesis are more abundant, as summarized in Tables 1.1– 1.5. After PSNL, CCI and SNL, TNF-α, IL-1β, IL-6, IFN-γ, RANTES/CCL5 (Regulated on Activation, Normal T cell Expressed and Secreted/ Chemokine (C-C motif) ligand 5) and GRO/KC (CXCL1) — growth-

DRG neurons as in the case of satellite cells (Hanani, 2005), but this was never proved so far. Contribution of resident macrophages and microglia A step forward in investigating the resident/endoneurial macrophage contribution to neuropathies was the use of bone marrow chimeric mice that allowed the differentiation between the resident macrophages and invading hematogenous macrophages (Mueller et al., 2008). This study confirmed previous observations that this population, accounting for 2–4% of the total endoneurial cell population (Oldfors, 1980), activates earlier than hematogenous macrophages, proliferates and shares activation features similar to microglia (Mueller et al., 2001, 2003). The hematogenous macrophages supplemented the resident response only in some parts of the peripheral nerves. However, this observation does not imply that the hematogenous response is always following the resident response. Depending on the lesion, one component might activate faster, could be the only component of the response or they could supplement each other. Until now a comparison from this perspective of the two populations of macrophages was not yet performed, possibly because of a lack of experimental data as indicated below. In the sciatic nerve, there is only one study in a crushed pain model, showing that resident Iba-1 (+) macrophages significantly increase before hematogenous macrophage infiltration (Table 1.3). In DRG, Iba-1 (+) and ED-2 (+) resident macrophages remain scattered

Table 1.3 Immune profile of peripheral nervous system in traumatic-induced neuropathic pain models. Pain model

Parameter

Hours

Sciatic nerve Days Weeks

Hours

Macrophages/ microglia

Sciatic nerve ligation/ transection or L5 dorsal or ventral root transection

TNF-α

IL-1β

ED-1 L5 (7)

Cyto kines/ chemo kines

IL-18

p-p38 ipsi-L5 dorsal horn (2)

References Hu and McLachlan, 2002 Hu et al., 2007 Dubovy et al., 2007 Dubovy et al., 2006 Kim et al., 2011 Hu and McLachlan, 2003 Xu et al., 2007

Xu et al., 2007 Cheng et al., 2003

Dubovy et al., 2006

Iba-1 ipsidorsal horn (7)

Satellite cells (2) ED-1 (2-4)

p-p38 ipsi-L5 dorsal horn (1)

Weeks OX-42 ipsidorsal horn (2)

Kim et al., 2011

ED-1 (2-4, 8) Iba-1 (3)

TNF-α

Spinal cord Days OX-42 laminae I-IV of ipsidorsal horn and ventral horn (7)

ED-1 satellite cells L4-L5 (2)

p-p38 Schwann cells, less in ED1 (8)

Kinases

Hours

pERK1/2 ipsi-L5 dorsal horn (24-48) ED-1 satellite cells L4-L5 (7)

Macrophages/ microglia

L5 spinal nerve or sciatic nerve crush

Weeks MHC-II (few AN) L4-L5 (11) ED1 (mostly AN) L5 (2, 4)

pERK1/2 satellite cells L5 (24-48)

Kinases

Cyto kines/ chemo kines

DRG Days MHC-II ED2 ED1 OX-42 (mostly BN) L4-L5 (7)

ED-1 satellite cells (3)

Iba-1 ipsidorsal horn (3)

Menge et al., 2001 Myers et al., 2003 Mueller, et al., 2001 Mueller, et al., 2003 George et al., 2004 Hatashita, et al., 2008 Myers et al., 2003

Hatashita, et al., 2008 George et al., 2004

Menge et al., 2001

Note: The color code indicates the references associated with a particular tissue. The italic letters indicate a correspondence between a certain parameter and a specific reference. MHC-II (major histocompatibility complex-class II), OX-42/CD11b, ED1/CD68, Iba-1 (ionized binding adapter protein-1) — are specific macrophages/microglia markers. p-p38 (phospho-p38), p-ERK1/2 (phospho-Extracellular Signal-Regulated Kinase). The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L4…L6 represent the ipsilateral DRG where the particular aspect was investigated. BN — distribution between neurons. AN — ring-distribution around neurons, beneath satellite cells sheath (Cheng et al., 2003; Dubovy et al., 2006; Dubovy et al., 2007; George et al., 2004; Hatashita et al., 2008; Hu and McLachlan, 2002; Hu and McLachlan, 2003; Hu et al., 2007; Kim et al., 2011; Menge et al., 2001; Mueller et al., 2001; Mueller et al., 2003; Myers et al., 2003; Xu et al., 2007).

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Table 1.4 Immune profile of peripheral nervous system in traumatic-induced neuropathic pain models. Pain model

Parameter

Hours

Sciatic nerve Days Weeks

Hours

Macrophages/ microglia

Kinases

SNL

TNF-α

IL-6 Cyto kines/ chemo kines

DRG Days ED-1 L5 (7) Iba-1 L5 (5)

p-p38 satellite cells L5 (3 or 7) p-ERK1/2 satellite cells L5 (7-10) p-ERK5 GFAP (+) satellite cells L5 (7)

p-p38 satellite cells L5 (3) p-ERK1/2 satellite cells L5 (3)

Satellite cells L4-L5 (7) All tissue L4-L5 (3) ED-1 (7)

Satellite cells L4-L5 (2)

IL-18

CXCL1

Weeks ED-1 (mostly AN) L5 (2)

All tissue L4-L5 (3)

Hours

Spinal cord Days OX-42 Iba-1 ipsidorsal horn. (3, 7, 10)

p-p38 ipsi-L5 dorsal horn (3) p-ERK1/2 ipsi-L5 dorsal horn (1-10) p-ERK5 laminae I-III ipsi-L5 dorsal horn (7)

Weeks

p-p38 ipsi-L5 dorsal horn (3)

References Dubovy et al., 2006 Miyoshi et al., 2008 Scholz et al., 2008 Jin, et al., 2003 Terayama et al., 2008 Zhuang et al., 2005 Obata, et al., 2007 Ton et al., 2013 Jin, et al., 2003 Terayama et al., 2008 Obata, et al., 2004 Zhuang et al., 2005 Obata, et al., 2007

Dubovy et al., 2006

Li et al., 2007

Iba-1 laminae I-III ipsi-L5 dorsal horn (7)

Miyoshi et al., 2008

Li et al., 2007

Note: The color code indicates the references associated with a particular tissue. The italic letters indicate a correspondence between a certain parameter and a specific reference. SNL — spinal nerve ligation. OX-42/CD11b, ED1/CD68, Iba-1 (ionized binding adapter protein-1) — are specific macrophages/microglia markers. p-p38 (phospho-p38), p-ERK1/2 or p-ERK5 (phospho-Extracellular Signal-Regulated Kinase). GRO/KC (CXCL1) — growth-related oncogene chemokine. The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L4…L6 represent the ipsilateral DRG where the particular aspect was investigated. AN — ring-distribution around neurons, beneath satellite cells sheath (Dubovy et al., 2006; Jin et al., 2003; Li et al., 2007; Miyoshi et al., 2008; Obata et al., 2004; Obata et al., 2007; Scholz et al., 2008; Terayama et al., 2008; Ton et al., 2013; Zhuang et al., 2005).

related oncogene chemokine were detected in the whole piece of sciatic nerve, DRG or spinal cord tissue (Tables 1.1, 1.2 and 1.4). A macrophage contribution could be assumed in this case, but it would require a confirmation. After sciatic nerve ligation, sciatic nerve crush, SNL and lumbar disk herniation, TNF-α was located in the satellite cells around DRG neurons (Tables 1.3, 1.4 and 1.5). These cells were considered satellite based on their anatomic distribution, and not because they expressed specific markers like vimentin or S100A9 (Ton et al., 2013). Knowing that macrophages do dispose sometimes as satellite cells, as mentioned above, a macrophage contribution could also be assumed in this case, but again it would require a confirmation. Specific kinases activated in traumatic-induced neuropathic pain models Because the resident macrophages are descendants of the same myeloid progenitor cells as microglia (Rio-Hortega, 1932; Saijo and Glass, 2011) and in the healthy PNS might have the same function of continuously screening the homeostasis of the endoneurial environment as microglia do inside CNS (Nimmerjahn et al., 2005), we explored whether there are data showing that they share with microglia other traits beside cytokine/chemokine secretion. After an insult to the CNS or PNS, microglia activate, displaying an up-regulation of kinases in addition to specific morphologic changes. Most frequently, increased p-p38,

p-ERK1/2 or p-ERK5 has been identified in microglia after SNI, L5 dorsal or ventral root transection and SNL (Tables 1.2, 1.3 and 1.4). Similarly to microglia, after an insult to PNS resident macrophages rapidly activate, proliferate and become hypertrophic (Mueller et al., 2001; VegaAvelaira et al., 2009). The same kinases as in microglia were identified in GFAP (+) or non-identified satellite cells of L5 DRG after L5 dorsal root transection or SNL (Tables 1.3 and 1.4) or in the Schwann cells after PSNL and sciatic nerve crush (Tables 1.1 and 1.3). No macrophage subtype identified with a specific marker was associated with these particular kinases up-regulation. To summarize, in traumatic-induced neuropathic pain models no macrophage activation was detected hours after the lesion. Increased secretion of TNF-α after CCI (Table 1.2) and an upregulation of p-ERK1/2 after dorsal and ventral root transection (Table 1.3) were detected very early, but their cellular origin is not known. The earliest time point of activation was 1 day after the lesion, when mainly hematogenous macrophages activated in sciatic nerve and DRG, besides microglia in the spinal cord (Fig. 1). Endogenous macrophages started to activate 2–3 days later. The highest time point of activation was at 7 days after the lesion, but this could also be due to more existing data for this time point. We can't really talk about a particular macrophage subtype more readily activated than another or about a particular pain model more prone to activate the macrophages.

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Table 1.5 Immune profile of peripheral nervous system in traumatic-induced neuropathic pain models. Pain model

Parameter

Hours

Sciatic nerve Days Weeks

Hours

Macrophages/ microglia Lumbar disc herniation Cyto kines/ chemo kines

L5 DRG/ Trigeminal compresion

TNF-α

Macrophages/ microglia

Cyto kines/ chemo kines

TNF-α

DRG Days ED-1 L4-L5 (1, 7) Iba-1 L5 (7)

Weeks

Hours

Spinal cord Days

Weeks

Otoshi et al., 2010

Iba-1 satellite cells L5 (7) ED-1 L5 (7)

References Obata et al., 2002 Otoshi et al., 2010

OX-42 spinal trigeminal nucleus (10)

Ma et al., 2012 Watanabe et al., 2011

Watanabe et al., 2011

ED-1 L5 (7)

Note: The color code indicates the references associated with a particular tissue. The italic letters indicate a correspondence between a certain parameter and a specific reference. OX-42/CD11b, ED1/CD68, Iba-1 (ionized binding adapter protein-1) — are specific macrophages/microglia markers. The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L4…L6 represent the ipsilateral DRG where the particular aspect was investigated. (Ma et al., 2012; Obata et al., 2002; Otoshi et al., 2010; Watanabe et al., 2011).

Metabolic-induced neuropathic pain model Diabetic neuropathy Immune cells and inflammatory mediators have been associated with type 1 diabetes-induced painful neuropathy. Depletion of peripheral macrophages with clodronate reduced diabetes-induced mechanical allodynia without affecting thermal hyperalgesia (Mert et al., 2009). Similarly, gabapentin (Wodarski et al., 2009), minocycline (Pabreja et al., 2011), lidocaine (Suzuki et al., 2011) and MAPK inhibitors (Sweitzer et al., 2004; Tsuda et al., 2008) that prevented or reversed microglia activation, attenuated the development of diabetic neuropathic pain. Given all that, it was interesting to know at which time point the macrophages activate, so that a therapy could be initiated to prevent further disease progression. Similar to traumatic neuropathic pain models, in the diabetic sciatic nerve the hematogenous ED-1 (+) macrophages were detected earlier than the resident Iba-1(+) macrophages (2 weeks vs 8 weeks) (Table 2.1). However, in the L4–L5 DRG and in the medial part of the dorsal horn resident macrophages and microglia did activate at only 1 week after STZ-induced diabetes (Table 2.1), suggesting a higher susceptibility of these tissues to associated hyperglycemia. Increased levels of p-ERK1/2, p-p38, p-SFK (Src-Family Kinase) and p-JNK were specifically associated with microglia, but in the sciatic nerve and DRG their origin is unclear (Table 2.1). Among cytokines/chemokines, some have been associated with type-1 diabetes (Skundric and Lisak, 2003). TNF-α IL-1β and IL-6 were up-regulated in the sciatic nerve and spinal cord, but only IL-1β was co-located with ED-1 (+) macrophages in the sciatic nerve (Table 2.1). TNF-α was specifically co-located with the Schwann cells and ED-1 (+) macrophages in the sural nerve of patients with established (10–12 months) diabetic lumbosacral radiculoplexus neuropathy (Kawamura et al., 2008), but this was not a pain model.

intoxication. In the proximal part of the nerve, more resident Iba-1 (+)/ GFP− endoneurial macrophages have been detected, whereas in distal parts a minor influx of ED-1 (+)/GFP+ hematogenous macrophages was observed (Table 2.1). Increased levels of IL-10 and CCL2 at proximal level and TNF-α and IL-6 at distal level were also measured, although they were not specifically located with the endoneurial macrophages (Table 2.1). IL-10 cytokine has anti-inflammatory properties, so its secretion is associated more with healing than with pain.

Cancer chemotherapy-induced peripheral neuropathy (CIPN) Cancer chemotherapy with vincristine, paclitaxel, oxaliplatin, cisplatin and bortezomib frequently induce peripheral neuropathy (Jaggi and Singh, 2012). The incidence of CIPN varies from 3–7% with one agent, up to 38% with combination regimens (Connelly et al., 1996). Of all these anti-cancer drugs, only for paclitaxel and vincristine there are some studies indicating a possible contribution of the immune system to the neuropathy associated with their administration. Low-dose paclitaxel treatment (4–8 mg/kg) was associated with increased levels of IL-1β, IL-6 and TNF-α in the lumbar spinal cord, which decreased later even though OX-42 (+) microglia were still up-regulated (Table 2.2). Moderate-dose paclitaxel treatment (24 mg/kg) induced a persisted, gradual mechanical allodynia which was associated with significant increase of ED-1 (+) macrophages in L4 DRG (Table 2.2). Vincristine administration was associated with increased activation of F4/80 macrophages that secreted IL-6 in sciatic nerve and L4–L6 DRG, together with increased activation of spinal cord Iba-1 (+) microglia that secreted TNF-α (Table 2.2).

Infection-induced neuropathic pain models

Neurotoxic-induced neuropathic pain models

HIV-1 gp120 induced neuropathy

Acrylamide-induced neuropathy

People living with HIV (human immunodeficiency virus type 1) frequently complain of painful neuropathy. The HIV coat protein gp120 (glycoprotein 120) was implicated in its pathogenesis, through the neurotoxic cascade initiated via interaction with CXCR4 and/or CCR5 chemokine receptors (Verma et al., 2005). In rat sciatic nerve, perineural administration of gp120 was associated with ED-1 (+) macrophage infiltration at the site of administration or at distal level, and with OX-42 (+) microglia activation (Table 2.1).

Acrylamide intoxication induces a distal, length-dependent axonal degeneration and therefore is used as an experimental model to study the pathogenesis of distal peripheral neuropathies (Griffin et al., 1977). In sciatic nerve of bone marrow chimeric mice carrying GFP (green fluorescent protein), acrylamide-induced neuropathy was associated with an increased response of endoneurial macrophages after the

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877

Table 2.1 Immune profile of peripheral nervous system in metabolically/chemically-induced neuropathic pain models. Pain model

Parameter

Macrophages/ microglia

Diabetic neuropathy

Hours

Sciatic nerve Days Weeks ED-1 (2-3,12) Iba-1 (8)

pERK1/2 all tissue (12) Kinases

Cyto kines/ chemo kines

IL-1β

IL-6

IL-10

MCP-1/ CCL2 HIV-1 gp120 induced neuropathy

Weeks Iba-1 (4)

Hours

Spinal cord Days

pERK1/2 p-p38 p-JNK p-SFK all tissue L4-L5 (3-4)

Macrophages/ microglia

ED-1 proximal (7)

Weeks Iba-1 OX-42 medial dorsal horn (1-4) pERK1/2 p-p38 p-JNK p-SFK OX-42 (3-4) all tissue (12) All tissue (5) All tissue (5) All tissue (5)

IL-6

TNF-α

Cyto kines/ chemo kines

DRG Days Iba-1 (7)

All tissue (10) ED-1 (3)

TNF-α

Macrophages/ microglia

Acrylamideinduced neuropathy

Hours

References Conti et al., 2002 Nukada et al., 2011 Yamagishi et al., 2008 Tsuda et al., 2008 Ton et al., 2013 Wodarski et al., 2009 Yamagishi et al., 2008 Daulhac et al., 2006 Tsuda et al., 2008

Drel et al., 2010 Bishnoi et al., 2011 Conti et al., 2002 Bishnoi et al., 2011 Bishnoi et al., 2011

Iba-/GFPproximal ED-1/ GFP+ distal (4)

Mueller et al, 2008

All tissue distal nerve (4) All tissue distal nerve (4) All tissue proximal nerve (4) All tissue proximal nerve (4) ED-1 distal (2)

Mueller et al, 2008

Mueller et al, 2008

Mueller et al, 2008

Mueller et al, 2008

OX-42 dorsal horn (5)

Wallace et al., 2007 Herzberg and Sagen, 2001

Note: OX-42/CD11b, ED-1/CD68, Iba-1 (ionized binding adapter protein-1) are specific macrophages/microglia markers. MCP-1/CCL2 — monocyte chemotactic protein-1/Chemokine (C–C motif) ligand 2. p-p38 (phospho-p38), p-ERK1/2 (phospho-Extracellular Signal-Regulated Kinase), SFK (Src-family kinases), p-JNK (c-Jun N-terminal kinase). The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L2–L5 represent the DRG where the particular aspect was investigated (Bishnoi et al., 2011; Conti et al., 2002; Daulhac et al., 2006; Drel et al., 2010; Herzberg and Sagen, 2001; Mueller et al., 2008; Nukada et al., 2011; Ton et al., 2013; Tsuda et al., 2008; Wallace et al., 2007; Wodarski et al., 2009; Yamagishi et al., 2008).

Post-herpetic neuralgia Postherpetic neuralgia (PHN) is often the consequence of varicellazoster virus infection. This virus causes varicella (chicken pox) followed by a lifelong latency in ganglia, from where it reactivates to produce herpes zoster (shingles). Clinically, herpes zoster is associated with severe, acute pain and very often with chronic postherpetic neuralgia that can last for years. In the very few studies exploring the immune cells' contribution to PHN pathogenesis, it was shown that in human ganglia (trigeminal, L2 and C1 DRG), 1 to 4.5months after virus infection there was a strong ED-1 macrophage infiltration (Table 2.2), and in a rat pain model of PHN, spinal astrocyte but not microglia contributed to the chronic pain (Zhang et al., 2011).

and injure the terminal endings of the sensory fibers that innervate the periosteum and the mineralized bone, which subsequently leads to specific activation of neurons and immune cells in the DRG and spinal cord. In a cancer-induced bone pain model generated with intramedullarly mammary gland carcinoma, prostate cancer or osteolytic tumor cell inoculation in the tibia or femur, OX-42 (+) and Iba-1 (+) spinal cord microglia became hypertrophic and expressed increased level of p-ERK1/2, and scattered ED-1 macrophages invaded the L2 DRG (Table 2.2). Intrathecal minocycline significantly reduced the microglia increase and the associated pain (Wang et al., 2012a). Tumor-induced activation of the spinal cord was accompanied by increased levels of TNF-α IL-1β, IL-6 and MCP-1, although they were not specifically associated with a particular cell type (Table 2.2).

Tumor invasion-induced neuropathic pain models Conclusions Cancer-induced bone pain Metastatic breast, prostate or lung cancer is associated with bone cancer pain, a severe, debilitating condition which can be difficult to treat (Mercadante, 1997). Tumor cells that invade the bone, contact

There is a significant body of evidence that macrophages and their CNS resident counterparts – microglia – are active participants in the generation of neuropathic pain. In this review an analysis of their contribution to neuropathic pain development in terms of time, place

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Table 2.2 Immune profile of peripheral nervous system in metabolically/chemically-induced neuropathic pain models. Pain model

Parameter

Hours

Sciatic nerve Days Weeks F4/80 (7)

Hours

Macrophages/ microglia Cancer chemotherapyinduced peripheral neuropathy (vincristine and paclitaxel)

DRG Days F4/80 L4-L6 (7) ED-1 L4 (4)

Weeks

IL-1β IL-6

F4/80 (7)

Macrophages/ microglia

F4/80 L4-L6 (7) ED-1 L2 (2)

Kinases Cancerinduced bone pain

IL-1β IL-6 MCP-1

Post-herpetic neuralgia

Macrophages/ microglia

Weeks OX-42 dorsal and ventral horn (4-6)

ED-1 (4-16)

References Kiguchi et al., 2008a Kiguchi et al., 2008b Liu et al., 2010 – moderate dose Ledeboer et al., 2007 - low dose Burgos et al., 2012 - low dose Kiguchi et al., 2008a Burgos et al., 2012 - low dose

Burgos et al., 2012 - low dose Kiguchi et al., 2008b Burgos et al., 2012 - low dose

OX-42 dorsal and ventral horn (6, 8)

OX-42 Iba-1 dorsal horn (2-3)

p-ERK1/2 OX-42 (6)

pERK1/2 Iba-1 (2-3)

All tissue (12) All tissue (12) All tissue (12) All tissue (6-18)

TNF-α Cyto kines/ chemo kines

Spinal cord Days Iba-1 (7)

Iba-1 (7) all tissue (4 and 8) All tissue (4 and 8) All tissue (4 and 8)

TNF-α Cyto kines/ chemo kines

Hours

Mao-Ying et al. 2012 Wang et al. 2011 Peters et al. 2005 Zhang et al. 2005 Wang et al. 2012b Wang et al. 2011 Wang et al. 2012b

Mao-Ying et al. 2012 Mao-Ying et al. 2012 Mao-Ying et al. 2012 Hu et al. 2012 Gowrishankar et al. 2010

Note: OX-42/CD11b, ED-1/CD68, Iba-1 (ionized binding adapter protein-1), F4/80 are specific macrophages/microglia markers. MCP-1/CCL3 — monocyte chemotactic protein-1/ Chemokine (C–C motif) ligand 2. p-ERK1/2 (phospho-Extracellular Signal-Regulated Kinase). The numbers in brackets represent the number of hours/days/weeks when a significant increase was noticed. L2–L5 represent the DRG where the particular aspect was investigated (Burgos et al., 2012; Gowrishankar et al., 2010; Hu and McLachlan, 2003; Hu et al., 2012; Kiguchi et al., 2008a; Kiguchi et al., 2008b; Ledeboer et al., 2007; Liu et al., 2010; Mao-Ying et al., 2012; Peters et al., 2005; Wang et al., 2011; Wang et al., 2012b; Zhang et al., 2005).

and subtype's activation profile (kinase up-regulation and cytokine/ chemokine secretion) was made, with the goal to identify a possible pattern associated with a particular pain model that could be used for further specific targeted therapy. Knowing that both types of cells display a remarkable plasticity and are able to tune their physiology according to microenvironmental signals, it was no surprise to notice that in most pain models both hematogenous and resident macrophages/microglia were involved, except for SNI and PHN where only the resident and respectively, the hematogenous ones were described. Although the hypothesis was that macrophages could have the same hallmark of activation as microglia (i.e. kinase upregulation), this hasn't been proved in any pain models. There is the possibility for the satellite cells expressing up-regulated kinases in sciatic nerve transection and SNL to be the hematogenous (Dubovy et al., 2006, 2007) or endogenous (Ton et al., 2013) macrophages that have been shown to dispose around DRG neurons as perineuronal rings. However, the hematogenous macrophages were not investigated on this matter, and we showed that after SNL the endogenous Iba-1 (+) macrophages in the DRG didn't express any kinases (Ton et al., 2013). So, even though we could say at this moment that macrophages didn't respond with kinase up-regulation, there are still many pain models to explore to fully answer this question. In addition, the cytokines/ chemokines that have been identified as secreted by macrophages inside sciatic nerve and DRG were of hematogenous origin in most pain models, except for lumbar disk herniation in which endogenous Iba-1 (+) secreted TNF-α (Table 1.5). This observation points to the fact that although endogenous macrophages seem to be involved in many pain models and could respond faster than the hematogenous

macrophages, their contribution to neuropathic pain pathogenesis is still unclear. All together, the overview shows that although a significant progress has been made, data in the literature are still scarce and scattered and we can't really talk about a macrophage map associated with neuropathic pain models. There might be several reasons for this: (1) not all the macrophage subtypes have been analyzed for all pain models, so it is not clear yet if one subtype is more important than the other for a particular case; (2) it is not completely clear how they contribute to specific pain events: it could be through cytokine/chemokine secretion – although not all the analyzed subtypes have been investigated for this aspect, or it could be through specific gap junctions that develop between macrophages and DRG neurons – which, however, have never been proved so far; (3) although macrophages share a common origin with microglia, they seem to have a different physiology because they do not respond with kinase up-regulation after a lesion. As the first sensors of danger, the therapeutic potential of macrophages is undoubtedly big, but because they are so versatile and they do not have only neurotoxic effects, but also healing and regulatory properties, additional data about their physiology is still required. To progress in this direction and better harvest their potential, there are still some questions to be answered, which could clarify the aspects above. Is there a pattern of activated macrophages specific to each neuropathic pain or only a particular type is mainly involved? What is their maximum time of activation depending on the lesion — hours, days or weeks? How are they involved in different neuropathic pain events: through direct contact or in a paracrine manner? Do they express specific markers that would help targeting them with high

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specificity, in order to limit side effects? Future studies to answer these questions will allow a better understanding of macrophage physiology and could open future clinical development pathways for other neuropathic pain treatments. Conflict of interest statement None.

Acknowledgments This work was supported by the Romanian National Authority for Scientific Research, CNCS — UEFISCDI (project ID — IDEAS 117/2011). Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.lfs.2013.10.005. References Alexander JK, Cox GM, Tian JB, Zha AM, Wei P, Kigerl KA, et al. Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress. Exp Neurol 2012;236:351–62. Bishnoi M, Bosgraaf CA, Abooj M, Zhong L, Premkumar LS. Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators. Mol Pain 2011;7:52. Burgos E, Gomez-Nicola D, Pascual D, Martin MI, Nieto-Sampedro M, Goicoechea C. Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells. Eur J Pharmacol 2012;682:62–72. Cheng XP, Wang BR, Liu HL, You SW, Huang WJ, Jiao XY, et al. Phosphorylation of extracellular signal-regulated kinases 1/2 is predominantly enhanced in the microglia of the rat spinal cord following dorsal root transection. Neuroscience 2003;119: 701–12. Connelly E, Markman M, Kennedy A, Webster K, Kulp B, Peterson G, et al. Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpected incidence of neurotoxicity. Gynecol Oncol 1996;62:166–8. Conti G, Scarpini E, Baron P, Livraghi S, Tiriticco M, Bianchi R, et al. Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1beta and p75NTR. J Neurol Sci 2002;195:35–40. Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, 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;70:1246–54. Drel VR, Lupachyk S, Shevalye H, Vareniuk I, Xu W, Zhang J, et al. New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-{alpha}. Endocrinology 2010;151: 2547–55. Dubovy P. Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction. Ann Anat 2011;193:267–75. Dubovy P, Jancalek R, Klusakova I, Svizenska I, Pejchalova K. Intra- and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol 2006;26:1205–17. Dubovy P, Tuckova L, Jancalek R, Svizenska I, Klusakova I. Increased invasion of ED-1 positive macrophages in both ipsi- and contralateral dorsal root ganglia following unilateral nerve injuries. Neurosci Lett 2007;427:88–93. Dubovy P, Klusakova I, Svizenska I, Brazda V. Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain. Histochem Cell Biol 2010;133: 323–37. Ducreux D, Attal N, Parker F, Bouhassira D. Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia. Brain 2006;129:963–76. Echeverry S, Wu Y, Zhang J. Selectively reducing cytokine/chemokine expressing macrophages in injured nerves impairs the development of neuropathic pain. Exp Neurol 2012;240:205–18. Feng X, Zhang F, Dong R, Li W, Liu J, Zhao X, et al. Intrathecal administration of clonidine attenuates spinal neuroimmune activation in a rat model of neuropathic pain with existing hyperalgesia. Eur J Pharmacol 2009;614:38–43. George A, Buehl A, Sommer C. Wallerian degeneration after crush injury of rat sciatic nerve increases endo- and epineurial tumor necrosis factor-alpha protein. Neurosci Lett 2004;372:215–9. Ghanouni P, Behera D, Xie J, Chen X, Moseley M, Biswal S. In vivo USPIO magnetic resonance imaging shows that minocycline mitigates macrophage recruitment to a peripheral nerve injury. Mol Pain 2012;8:49.

879

Gomez-Nicola D, Valle-Argos B, Suardiaz M, Taylor JS, Nieto-Sampedro M. Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration. J Neurochem 2008;107:1741–52. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5: 953–64. Gosselin RD, Suter MR, Ji RR, Decosterd I. Glial cells and chronic pain. Neuroscientist 2010;16:519–31. Gowrishankar K, Steain M, Cunningham AL, Rodriguez M, Blumbergs P, Slobedman B, et al. Characterization of the host immune response in human ganglia after herpes zoster. J Virol 2010;84:8861–70. Griffin JW, Price DL, Drachman DB. Impaired axonal regeneration in acrylamide intoxication. J Neurobiol 1977;8:355–70. Hanani M. Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 2005;48:457–76. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007;10:1387–94. Hatashita S, Sekiguchi M, Kobayashi H, Konno S, Kikuchi S. Contralateral neuropathic pain and neuropathology in dorsal root ganglion and spinal cord following hemilateral nerve injury in rats. Spine (Phila Pa 1976) 2008;33:1344–51. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol 2001;116:29–39. Hu P, McLachlan EM. Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience 2002;112:23–38. Hu P, McLachlan EM. Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat. Exp Neurol 2003;184:590–605. Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 2007;21:599–616. Hu JH, Zheng XY, Yang JP, Wang LN, Ji FH. Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer-induced bone pain in rats. Neurosci Lett 2012;517:60–3. Jaggi AS, Singh N. Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology 2012;291:1–9. 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;23:4017–22. Kawamura N, Dyck PJ, Schmeichel AM, Engelstad JK, Low PA. Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol 2008;115:231–9. 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;28:5189–94. Kiguchi N, Maeda T, Kobayashi Y, Kishioka S. Up-regulation of tumor necrosis factor-alpha in spinal cord contributes to vincristine-induced mechanical allodynia in mice. Neurosci Lett 2008a;445:140–3. Kiguchi N, Maeda T, Kobayashi Y, Kondo T, Ozaki M, Kishioka S. The critical role of invading peripheral macrophage-derived interleukin-6 in vincristine-induced mechanical allodynia in mice. Eur J Pharmacol 2008b;592:87–92. Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Activation of extracellular signal-regulated kinase in sciatic nerve contributes to neuropathic pain after partial sciatic nerve ligation in mice. Anesth Analg 2009;109:1305–11. Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation. Pain 2010;149:305–15. Kim CF, Moalem-Taylor G. Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res 2011;1405:95–108. Kim D, You B, Lim H, Lee SJ. Toll-like receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury. Mol Pain 2011;7:74. Komori T, Morikawa Y, Inada T, Hisaoka T, Senba E. Site-specific subtypes of macrophages recruited after peripheral nerve injury. Neuroreport 2011;22:911–7. Latremoliere A, Mauborgne A, Masson J, Bourgoin S, Kayser V, Hamon M, et al. Differential implication of proinflammatory cytokine interleukin-6 in the development of cephalic versus extracephalic neuropathic pain in rats. J Neurosci 2008;28:8489–501. Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, et al. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 2007;21:686–98. Lee S, Zhang J. Heterogeneity of macrophages in injured trigeminal nerves: cytokine/chemokine expressing vs. phagocytic macrophages. Brain Behav Immun 2012;26:891–903. Li H, Xie W, Strong JA, Zhang JM. Systemic antiinflammatory corticosteroid reduces mechanical pain behavior, sympathetic sprouting, and elevation of proinflammatory cytokines in a rat model of neuropathic pain. Anesthesiology 2007;107:469–77. Lin CS, Tsaur ML, Chen CC, Wang TY, Lin CF, Lai YL, et al. Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pain in rats. Reg Anesth Pain Med 2007;32:209–16. Lin SC, Yeh JH, Chen CL, Chou SH, Tsai YJ. Effects of local lidocaine treatment before and after median nerve injury on mechanical hypersensitivity and microglia activation in rat cuneate nucleus. Eur J Pain 2011;15:359–67. Liou JT, Mao CC, Ching-Wah Sum D, Liu FC, Lai YS, Li JC, et al. Peritoneal administration of Met-RANTES attenuates inflammatory and nociceptive responses in a murine neuropathic pain model. J Pain 2013;14:24–35.

880

V. Ristoiu / Life Sciences 93 (2013) 870–881

Liu T, van Rooijen N, Tracey DJ. Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain 2000;86:25–32. Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, et al. Prevention of paclitaxel-induced allodynia by minocycline: effect on loss of peripheral nerve fibers and infiltration of macrophages in rats. Mol Pain 2010;6:76. Ma W, Quirion R. Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. J Neurochem 2005;93:664–73. Ma W, Quirion R. Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy. J Neurochem 2006;98:180–92. Ma F, Zhang L, Lyons D, Westlund KN. Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve. Mol Brain 2012;5:44. Maeda T, Kiguchi N, Kobayashi Y, Ozaki M, Kishioka S. Pioglitazone attenuates tactile allodynia and thermal hyperalgesia in mice subjected to peripheral nerve injury. J Pharmacol Sci 2008;108:341–7. Mao-Ying QL, Wang XW, Yang CJ, Li X, Mi WL, Wu GC, et al. Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats. Mol Brain 2012;5:16. Menge T, Jander S, Stoll G. Induction of the proinflammatory cytokine interleukin-18 by axonal injury. J Neurosci Res 2001;65:332–9. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69: 1–18. Mert T, Gunay I, Ocal I, Guzel AI, Inal TC, Sencar L, et al. Macrophage depletion delays progression of neuropathic pain in diabetic animals. Naunyn Schmiedebergs Arch Pharmacol 2009;379:445–52. Mika J, Osikowicz M, Rojewska E, Korostynski M, Wawrzczak-Bargiela A, Przewlocki R, et al. Differential activation of spinal microglial and astroglial cells in a mouse model of peripheral neuropathic pain. Eur J Pharmacol 2009;623:65–72. Mika J, Rojewska E, Makuch W, Przewlocka B. Minocycline reduces the injury-induced expression of prodynorphin and pronociceptin in the dorsal root ganglion in a rat model of neuropathic pain. Neuroscience 2010;165:1420–8. 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;28:12775–87. Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 2006;51:240–64. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008;8:958–69. Mueller M, Wacker K, Ringelstein EB, Hickey WF, Imai Y, Kiefer R. Rapid response of identified resident endoneurial macrophages to nerve injury. Am J Pathol 2001;159:2187–97. Mueller M, Leonhard C, Wacker K, Ringelstein EB, Okabe M, Hickey WF, et al. Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages. Lab Invest 2003;83:175–85. Mueller M, Wacker K, Getts D, Ringelstein EB, Kiefer R. Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: lessons from acrylamide-induced neuropathy. Glia 2008;56:1005–16. Myers RR, Heckman HM, Rodriguez M. Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice. Exp Neurol 1996;141:94–101. Myers RR, Sekiguchi Y, Kikuchi S, Scott B, Medicherla S, Protter A, et al. Inhibition of p38 MAP kinase activity enhances axonal regeneration. Exp Neurol 2003;184: 606–14. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005;308:1314–8. Nukada H, McMorran PD, Baba M, Ogasawara S, Yagihashi S. Increased susceptibility to ischemia and macrophage activation in STZ-diabetic rat nerve. Brain Res 2011;1373: 172–82. Obata K, Tsujino H, Yamanaka H, Yi D, Fukuoka T, Hashimoto N, et al. Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation. Pain 2002;99:121–32. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, 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;24:10211–22. Obata K, Katsura H, Mizushima T, Sakurai J, Kobayashi K, Yamanaka H, et al. Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain. J Neurochem 2007;102:1569–84. Oldfors A. Macrophages in peripheral nerves. An ultrastructural and enzyme histochemical study on rats. Acta Neuropathol 1980;49:43–9. Otoshi K, Kikuchi S, Konno S, Sekiguchi M. The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain-related behavior after application of nucleus pulposus onto the nerve root in rats. Spine (Phila Pa 1976) 2010;35:264–71. Pabreja K, Dua K, Sharma S, Padi SS, Kulkarni SK. Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms. Eur J Pharmacol 2011;661:15–21. Peters CM, Ghilardi JR, Keyser CP, Kubota K, Lindsay TH, Luger NM, et al. Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp Neurol 2005;193:85–100. Rio-Hortega PD. Cytology and cellular pathology of the nervous system. New York: P.B. Hoeber, Inc.; 1932.

Rutkowski MD, Pahl JL, Sweitzer S, van Rooijen N, DeLeo JA. Limited role of macrophages in generation of nerve injury-induced mechanical allodynia. Physiol Behav 2000;71: 225–35. Sacerdote P, Franchi S, Trovato AE, Valsecchi AE, Panerai AE, Colleoni M. Transient early expression of TNF-alpha in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy. Neurosci Lett 2008;436:210–3. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 2011;11:775–87. Saika F, Kiguchi N, Kobayashi Y, Fukazawa Y, Kishioka S. CC-chemokine ligand 4/macrophage inflammatory protein-1beta participates in the induction of neuropathic pain after peripheral nerve injury. Eur J Pain 2012;16:1271–80. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007;10:1361–8. Scholz J, Abele A, Marian C, Haussler A, Herbert TA, Woolf CJ, et al. Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats. Pain 2008;138:130–42. Shubayev VI, Myers RR. Endoneurial remodeling by TNFalph- and TNFalpha-releasing proteases. A spatial and temporal co-localization study in painful neuropathy. J Peripher Nerv Syst 2002;7:28–36. Skundric DS, Lisak RP. Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabesity Res 2003;4:303–12. Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004;361:184–7. Sommer C, Schafers M. Painful mononeuropathy in C57BL/Wld mice with delayed Wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res 1998;784:154–62. Stoll G, Griffin JW, Li CY, Trapp BD. Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation. J Neurocytol 1989;18:671–83. Suzuki N, Hasegawa-Moriyama M, Takahashi Y, Kamikubo Y, Sakurai T, Inada E. Lidocaine attenuates the development of diabetic-induced tactile allodynia by inhibiting microglial activation. Anesth Analg 2011;113:941–6. Sweitzer SM, Medicherla S, Almirez R, Dugar S, Chakravarty S, Shumilla JA, et al. Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model. Pain 2004;109:409–19. Terayama R, Omura S, Fujisawa N, Yamaai T, Ichikawa H, Sugimoto T. Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury. Neuroscience 2008;153:1245–55. Ton BH, Chen Q, Gaina G, Tucureanu C, Georgescu A, Strungaru C, et al. Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats. Acta Histochem 2013. http://dx.doi.org/10.1016/j.acthis.2013.04.007. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 2005;28:101–7. Tsuda M, Ueno H, Kataoka A, Tozaki-Saitoh H, Inoue K. Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia 2008;56:378–86. Vega-Avelaira D, Geranton SM, Fitzgerald M. Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Mol Pain 2009;5:70. Verma S, Estanislao L, Simpson D. HIV-associated neuropathic pain: epidemiology, pathophysiology and management. CNS Drugs 2005;19:325–34. Wallace VC, Blackbeard J, Pheby T, Segerdahl AR, Davies M, Hasnie F, et al. Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 2007;133:47–63. Wang LN, Yao M, Yang JP, Peng J, Peng Y, Li CF, et al. Cancer-induced bone pain sequentially activates the ERK/MAPK pathway in different cell types in the rat spinal cord. Mol Pain 2011;7:48. Wang LN, Yang JP, Zhan Y, Ji FH, Wang XY, Zuo JL, et al. Minocycline-induced reduction of brain-derived neurotrophic factor expression in relation to cancer-induced bone pain in rats. J Neurosci Res 2012a;90:672–81. Wang XW, Li TT, Zhao J, Mao-Ying QL, Zhang H, Hu S, et al. Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats. Neuroscience 2012b;217:172–81. Watanabe K, Yabuki S, Sekiguchi M, Kikuchi S, Konno S. Etanercept attenuates pain-related behavior following compression of the dorsal root ganglion in the rat. Eur Spine J 2011;20:1877–84. Webber C, Zochodne D. The nerve regenerative microenvironment: early behavior and partnership of axons and Schwann cells. Exp Neurol 2010;223:51–9. Whitehead KJ, Smith CG, Delaney SA, Curnow SJ, Salmon M, Hughes JP, et al. Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury. Brain Behav Immun 2010;24:569–76. Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M. Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain 2009;13:807–11. Woolf CJ. Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 2004;74:2605–10. Xu JT, Xin WJ, Wei XH, Wu CY, Ge YX, Liu YL, et al. p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury. Exp Neurol 2007;204:355–65. Yamagishi S, Ogasawara S, Mizukami H, Yajima N, Wada R, Sugawara A, et al. Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-gamma-ligand, in insulin-deficient diabetic rats. J Neurochem 2008;104:491–9.

V. Ristoiu / Life Sciences 93 (2013) 870–881 Zhang X, Mosser DM. Macrophage activation by endogenous danger signals. J Pathol 2008;214:161–78. Zhang RX, Liu B, Wang L, Ren K, Qiao JT, Berman BM, 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;118:125–36.

881

Zhang GH, Lv MM, Wang S, Chen L, Qian NS, Tang Y, et al. Spinal astrocytic activation is involved in a virally-induced rat model of neuropathic pain. PLoS One 2011;6:e23059. 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;114:149–59.