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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Exp Neurol. Author manuscript; available in PMC 2010 June 21.
Published in final edited form as:
PMCID: PMC2888707

Gliopathy Ensures Persistent Inflammation and Chronic Pain after Spinal Cord Injury

Claire E. Hulsebosch, Ph.D., Director, Mission Connect, Chair in Neurological Recovery, Vice-Chair and Professor


Research focused on improving recovery of function, including the reduction of central neuropathic pain (CNP) after spinal cord injury (SCI) is essential. After SCI, regional neuropathic pain syndromes above, at and below the level or spinal injury develop and are thought to have different mechanisms, but may share common dysfunctional glial mechanisms. Detloff et al, 2008 describes events in the lumbar region of the spinal cord after a midthoracic SCI injury, the so called “below-level” pain and compares the findings to peripheral nerve lesion findings. This commentary briefly reviews glial contributions and intracellular signaling mechanisms, both neuronal and glial, that provide the substrate for CNP after SCI, including the persistent glial production of factors that can maintain sensitization of dorsal horn neurons in segments remote from the spinal injury; ie. dorsal horn hyperexcitability to formerly non noxious stimuli that become noxious after SCI resulting in allodynia. The term “gliopathy” is proposed to describe the dysfunctional and maladaptive response of glial cells, specifically astrocytes and microglia, to neural injury that is initiated by the sudden injury induced increase in extracellular concentrations of glutamate and concomitant production of several proinflammatory molecules. It is important to understand the roles that different glia play in “gliopathy,” a condition that appears to persist after SCI. Furthermore, targeted treatment of gliopathy will attenuate mechanical allodynia in both central and peripheral neuropathic pain syndromes.


Research focused on improving recovery of function, including the reduction of central neuropathic pain (CNP) after spinal cord injury (SCI), is essential. The CNP syndromes or dysesthesias (disturbing somatic sensations that may not be painful) can be divided into two broad categories: 1) spontaneous pain – which occurs independently of peripheral stimuli, is persistent, waxes and wanes intermittently, and is described as numbness, burning, cutting, piercing or electric-like (Davidoff and Roth, 1991); 2) peripherally evoked pain – which occurs in response to either normally nonnoxious or noxious stimuli. The article in Experimental Neurology by Detloff et al., 2008 uses a rodent SCI model to address possible mechanisms that underlie neuropathic pain after SCI, a life long “secondary” symptom suffered by the majority of people with SCI (Hulsebosch, 2005). The Detloff article describes events in the lumbar region of the spinal cord after a midthoracic SCI injury, so called “below-level” pain and compares the findings to peripheral nerve lesion findings. To put the article in context, following SCI, people develop different regional syndromes. Siddall and colleagues (2002) defined three regional categories of pain that result from SCI: 1) above-level pain which occurs at dermatomes cranial to the injury site and occurs in areas where normal sensation persists following injury, 2) at-level pain which occurs in dermatomes near the spinal injury, develops shortly after SCI, and is often characterized as either stabbing pain or a stimulus independent type that is accompanied by allodynia (“girdle” or allodynia at the level of the sensory loss, Tasker and Dostrovsky, 1989), and 3) below-level pain which is localized to dermatomes distal to the injury site, develops more gradually than does at-level pain, and is often classified as a stimulus independent burning continuous pain (Sjolund, 2002; Vierck Jr et al., 2000). The current thinking is that the differential regional “pain syndromes” arise from differing mechanisms. However, we propose that there may be some common mechanisms which include abnormal glial functioning or “gliopathy” that ensure a persistent and chronic pain state.

The authors in the present article use evoked somatosensory tests to determine hindlimb mechanical allodynia (increased “pain-like” sensitivity in which formally nonnoxius stimuli becomes noxious) in a model of below level pain and report that increased microglia activation, as inferred by increased OX-42 immunoreaction product, correlated with increased “pain-like” behavior. Furthermore, activation of an intracellular signaling molecule, p38, is reported to be principally in neurons in the lumbar spinal cord. By contrast, our lab reports increased phosphorylation of p38 (p-p38, which is the activated form) in both microglia, astrocytes and neurons (see Crown et al., 2008) in regions immediately rostral to the spinal lesion (model of at level pain). Specifically, p38 MAP kinases are serine threonine kinases that are activated by several upstream kinases in response to inflammation. In turn, p-p38 plays a key role in monocyte/macrophage inflammatory responses and inhibition of p-p38 is associated with reduction in iNOS, TNF α, IL-1β, COX-2 and iNOS, all proinflammatory mediators known to be involved in neuropathic pain. Cellular localization of activated p38 is involved in neuronal and glial cell death, days after SCI (Crown et al., 2006), and is involved in persistent activation of both microglial and astrocytes (Zhuang et al., 2005; Svensson et al., 2005a,b; Hua et al., 2005) and in dorsal horn hyperexcitability (Crown et al., 2008), presumably by different pathways but possibly may share the same pathways in which the results are concentration dependent. In the latter case for example, p-p38 downstream activation of the transcription factor CREB can lead to feed forward phosphorylation of the NMDA receptors leading either to maintained hyperexcitability or neuronal death if sufficient numbers of NMDA are activated. It should be noted that there are two isoforms (p38α in neurons, p38β in microgial) so that selection of antibodies will determine cellular localization and may provide the reason for differential findings between laboratories.

We hypothesize that activation of the transcription factor CREB and ERK1/2 and p38 MAP kinase pathways play pivotal roles in persistent inflammation in the induction (which involves GABA neuronal death) and the maintenance phases of CNP after SCI (Crown et al., 2006,2008). Several studies support the important roles of these factors in peripheral neuropathic models (Milligan et al., 2003; Jin et al., 2003; Tsuda, et al., 2004; Svensson, et al., 2005a.b). Furthermore, we hypothesize that the increased expression of p-p38, p-ERK and p-CREB over time after SCI is in different cell populations, and in different cellular compartments reflecting either their role in apoptosis early after SCI (Zhuang et al., 2005) or their continued role in inflammation and/or persistent hyperexcitability (Crown et al., 2008). As a side note, certain MAP kinases, ERK, JNK and p38, are well known to be involved in cell apoptosis, and likely contribute to the early apoptotic events contributing to CNP after SCI, specifically demyelination of descending inhibitory circuits via oligoapoptosis (Finnerup, et al., 2003a,b,c; Beattie, et al., 2002) and loss of GABA cells (Rafati et al., 2008), both being mechanisms that contribute to the induction of chronic neuropathic pain via loss of inhibitory tone on somatosensory circuits (Finnerup, et al., 2003a,b,c; Gwak et al., 2008). The point is that the same molecules can have very different results depending on concentrations and temporal expression in a disease process (cell death vs. continued activation of intracellular signaling) that contributes to permanent neuronal hyperexcitability and resultant CNP.

In Detloff et al., 2008, the authors describe no significant increase in GFAP protein in the lumbar region, but increased GFAP mRNA in SCI groups compared to naïve. The increased GFAP is classically used as a “marker” of astrocytic activation which is known to occur after SCI and is also referred to as “reactive” astrocytes; although the significance of the increase GFAP is unknown. It is important to point out that Nesic et al., 2005 demonstrate significant GFAP protein increases from 4 hours up to 9 months after SCI in regions adjacent to the lesion (Fig.10a) and in lumbar and cervical regions (Fig.9a). Detloff et al., 2008 also conclude that an increase in proinflammatory cytokines correlated with the severity of below level chronic pain, although the source of the proinflammatory cytokines is unknown. The conceptual basis that increased severity of SCI corresponds to increased neuropathic pain was well described in previous manuscripts (Liu et al., 1997; Yezierski et al., 1998; Hao et al., 1991; Xu et al., 1992; Christensen and Hulsebosch, 1997) which indicate that the larger the lesion, the greater the area of allodynia. These observations were related to inflammation in a subsequent publication (DeLeo and Yezierski, 2001). Thus, given that inflammation follows CNS lesion, and greater lesions produce more inflammation, then the authors' conclusion is not too surprising, but it is important to have the correlation between proinflammatory cytokine levels and mechanical allodynia rigorously tested.

It is interesting to note that the mechanisms of the differential regional pain all appear to have early and permanent activation of both microglia and astrocytes in common (for below-level: Hains and Waxman, 2006, Gwak et al., 2008; for at level-Crown et al., 2008; for above level-Nesic et al., 2005). Perhaps the best of these studies is by Gwak et al., 2008. This study reports the use of the phosphosodiesterase inhibitor, propentofylline (PPF), which modulates both microglial and astrocytic activation (Tawfik, et al., 2007) given early after midthoracic SCI (Gwak et al., 2008). After midthoracic SCI, hindlimb mechanical allodynia occurs, that persists for the life of the subjects, accompanied by significant increases in GFAP and OX-42 immunoreaction product in the lumbar dorsal horn and significant development and persistence of dorsal horn neuron hyperexcitability, all which occur several segments remote from the SCI region. PPF administration for 7 days after SCI results in decreased changes in the lumbar cord that include decreased mechanical allodynia, decreased GFAP and OX-42 expression, and decreased glial (both astrocytic and microglia) soma hypertrophy (also a classical marker for activation), as well as decreased neuronal hyperexcitability, a fundamental substrate of central neuropathic pain (Hulsebosch, 2005 review). Thus, the conclusion is that inhibition of glia activation, both astrocytic and microglia, will improve chronic and persistent pain syndromes in remote segments below the level of lesion after SCI and in other central neuropathies. However, it is recognized that the mechanisms of astrocytic and microglial contributions to CNP are likely to be different.

In more recent work examining p38 activation, in astrocytes, microglia and dorsal horn neurons just rostral to the level of SCI, Crown et al., 2008 report that inhibiting the enzymatic activity of p38 MAPK reverses mechanical allodynia and decreases hyperexcitability in dorsal horn neurons. In addition, there is a SCI induced increase in GFAP and OX-42 protein expression which is attenuated by blocking activation of p38 MAPK. Thus, the conclusion is that glia activation, both astrocytic and microglia, have important roles in development and maintenance of persistent pain syndromes after SCI and other central neuropathies in regional neuropathic pain syndromes; and blocking specific intracellular signaling pathways can functionally alter the glia activation response. Genetic differences (Mills et al., 2001) and age at time of injury (Gwak et al., 2004) certainly play roles in neuropathic pain and genetic differences certainly play a role in cellular inflammatory responses (Popovich et al., 1997) and may explain differences between studies. However, irrespective of differences, the specific roles that glia populations play after SCI in central neuropathic pain are important to investigate.

To review, in the CNS there are two general types of macroglial cells: oligodendrocytes and astrocytes. Oligodendrocytes are the myelinating cells in the CNS, providing multiple and different axonal nodes (Schwann cells are the myelinating cells in the PNS). Thus, loss of oligodendrocytes after SCI or their dysfunction causes changes in conduction parameters not unlike demyelinating diseases. Astrocytes are classically thought to play roles in potassium, glutamate and other transmitter regulation and homeostasis in the extracellular and synaptic spaces through uptake mechanisms. Specialized astrocytes also play roles in the blood brain barrier and in neuronal nutritive functions (ex. satellite cells of dorsal root ganglion neurons). Microglia are classically thought to be principally phagocytes that are able to be mobilized after injury, infection, disease and in seizures. When activated, glia cells are known to hypertrophy, increase production of cell specific “markers” (GFAP for astrocytes and OX-42 for microglia and other macrophages) and produce proinflammatory cytokines, reactive oxygen species (ROS), ATP, excitatory amino acids, and nitric oxide (NO) (Johnstone et al., 1999; Martin, 1992; Piani et al., 1992; Shafer and Murphy, 1997; Tanaka et al., 1994); all of which are powerful candidates for mediating pain following neural injury and are known to produce neuronal hyperexcitability in dorsal horn neurons, a necessary substrate for neuropathic pain. Additionally, it is important to note that chronically activated astrocytes lead to permanent blood spinal cord barrier breakdown that ensure continued immune cell infiltration and feed forward continued activation of both astrocytes and microglia (Nesic et al., 2005).

In the mammalian system, we propose that normal glial function becomes abnormal and dysfunctional after CNS injury. The dysfunctional glial state contributes to conditions that initiate and ensure persistence of neuropathic pain. While the concept of glia-neuronal and neuronal-glial interactions were described in invertebrate systems several decades ago (see Lasek et al., 1974; Villegas, 1972); the conceptual basis of dysfunctional glial cells contributing to neuropathic pain is relatively new (Crown et al., 2008; Detloff, et al., 2008; DeLeo et al., 2006; Gwak et al., 2008; Nesic et al., 2005; Romero-Sandoval, et al., 2008; Milligan et al., 2008).

We propose the term “gliopathy” to describe the dysfunctional and maladaptive response of glial cells to neural injury. We hypothesize that the initiation of gliopathy after neural injury, is the sudden increase in the extracellular concentration of glutamate after peripheral nerve injury (Rooney et al., 2007) and after SCI (McAdoo, et al., 1999) that in some cases is 37 fold higher than resting concentrations and results in excitotoxicity (Xu et al., 2008) and glutamate receptor mediated sensitization of both neuronal and glial populations (Hulsebosch, 2005). With respect to the role of glutamate receptors in the dorsal horn excitability, we have published data that all three receptors are involved in CNP after SCI (Bennett et al., 2000; Mills et al., 2002; Hulsebosch, 2003). We know that NMDA receptor activation participates in the upregulation of several proinflammatory molecules (Nesic et al., 2002) and that proinflammatory cytokines exacerbate the glutamate mediated excitotoxicity after SCI (Hermann, et al., 2001). We hypothesize that one of the cellular sources for cytokine production immediately and for the first few days after SCI are from the dysfunctional glial cells (of course infiltrating cells are key contributors of proinflammatory cytokines and other sensitizing agents in early SCI (Fleming et al., 2006) and late in SCI (Nesic et al., 2005). Furthermore, we hypothesize that persistent and permanent glia dysfunction occurs in regions near as well as very remote from the spinal lesion and into the brain and that the dysfunctional glial cells continue to secrete proinflammatory cytokines and other sensitizing agents in both an autocrine and paracrine manner, creating persistent glial inflammation and continual sensitization of dorsal horn neurons.

It is obvious that the initial glutamate and proinflammatory cytokine increases that occur over the first few hours after SCI are not going to be useful therapeutic targets since most patients present to the emergency rooms 3 hours or later after injury. However, we propose the importance of understanding the roles that different glia play in “gliopathy,” a condition that appears to persist after SCI, and that the targeted treatment of gliopathy will attenuate mechanical allodynia in both central and peripheral neuropathic pain syndromes.


Requested Commentary of Detloff, et al., Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats, Exp. Neurol. (2008).

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Literature Cited

  • Beattie MS, Hermann GE, Rogers RC, Bresnahan JC. Cell death in models of spinal cord injury. Prog Brain Res. 2002;137:37–47. [PubMed]
  • Bennett AD, Everhart AW, Hulsebosch CE. Intrathecal NMDA and non-NMDA receptor antagonists reduce mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury. Brain Res. 2000;859:72–82. [PubMed]
  • Christensen MD, Hulsebosch CE. Chronic central pain after spinal cord injury. J Neurotrauma. 1997;14:517–537. [PubMed]
  • Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE. Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol. 2008 doi: 10.1016/j.expneurol.2008.05.025. [PMC free article] [PubMed] [Cross Ref]
  • Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases in the activated forms of ERK 1.2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol. 2006;199:397–407. [PubMed]
  • Davidoff G, Roth EJ. Clinical characteristics of central (Dysesthetic) pain in spinal cord injury patients. In: Casey KL, editor. Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press; New York: 1991. pp. 77–83.
  • DeLeo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: Path to CNS sensitization and chronic pain. Pain. 2006;122:17–21. [PubMed]
  • DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90:1–6. [PubMed]
  • Detloff MR, Fisher LC, McGaughy V, Longbrake EE, Popovich PG, Basso DM. Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol. 2008 doi: 10.1016/j.expneurol.2008.04.009. [PMC free article] [PubMed] [Cross Ref]
  • Finnerup NB, Gyldensted C, Nielsen E, Kristensen AD, Bach FW, Jensen TS. MRI in chronic spinal cord injury patients with and without central pain. Neurology. 2003a;61:1569–1575. [PubMed]
  • Finnerup NB, Johannesen IL, Bach FW, Jensen TS. Sensory function above lesion level in spinal cord injury patients with and without pain. Somatosensory Motor Res. 2003b;20:71–76. [PubMed]
  • Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS. Sensory function in spinal cord injury patients with and without central pain. Brain. 2003c;126:57–70. [PubMed]
  • Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE, Saenz AD, Pasquale-Styles M, Dietrich WD, Weaver LC. The cellular inflammatory response in human spinal cords after injury. Brain. 2006;129:3249–3269. [PubMed]
  • Gwak YS, Crown ED, Unabia GC, Hulsebosch CE. Protentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat. Pain. 2008 doi: 10.1016/j.pain.2008.01.021. [PMC free article] [PubMed] [Cross Ref]
  • Gwak YS, Hains BC, Johnson KM, Hulsebosch CE. Effect of age at time of spinal cord injury on behavioral outcomes in rat. J Neurotrauma. 2004;21:983–993. [PubMed]
  • Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26:4308–4317. [PubMed]
  • Hao JX, Xu XJ, Aldskogious H, Seiger A, Wiesenfield-Hallin Z. Allodynia-like effects in rat after ischemic spinal cord injury photochemically induced by laser irradiation. Pain. 1991;45:175–185. [PubMed]
  • Hermann GE, Rogers RC, Bresnahan JC, Beattie MS. Tumor-necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol Dis. 2001;8:590–599. [PubMed]
  • Hua XY, Svensson CI, Matsui T, Fitzsimmons B, Yaksh TL, Webb M. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci. 2005;22:2431–2440. [PubMed]
  • Hulsebosch CE. Mechanisms and treatment strategies for chronic central neuropathic pain after spinal cord injury. Top Spinal Cord Inj Rehabil. 2003;8:76–91.
  • Hulsebosch CE. From discovery to clinical trials: Treatment strategies for central neuropathic pain after spinal cord injury. Curr Pharm Design. 2005;11:1411–1420. [PubMed]
  • Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitrogen-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]
  • Johnstone M, Gearing AJ, Miller KM. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol. 1999;93:182–193. [PubMed]
  • Lasek RJ, Gainer H, Przybylski RJ. Transfer of newly synthesized proteins from Schwann cells to the squid giant axon. Proc Natl Acad Sci USA. 1974;71:1188–1192. [PubMed]
  • Liu S, Ruenes GL, Yezierski RP. NMDA and non-NMDA receptor antagonists protect against excitotoxic injury in the rat spinal cord. Brain Res. 1997;756:160–167. [PubMed]
  • Martin DD. Synthesis and release of neuroactive substances by glia cells. Glia. 1992;5:81–94. [PubMed]
  • McAdoo DJ, Xu GY, Robak G, Hughes MG. Changes in amino acid concentrations over time and space around an impact injury and their diffusion through the rat spinal cord. Exp Neurol. 1999;159:538–544. [PubMed]
  • Milligan ED, Sloane EM, Watkins LR. Glia in pathological pain: A role for fractalkine. J Neuroimmunol. 2008 Epub ahead of print. [PMC free article] [PubMed]
  • Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–1040. [PubMed]
  • Mills CD, Hains BC, Johnson KM, Hulsebosch CE. Strain and model differences in behavioral outcomes after spinal cord injury in rat. J Neurotrauma. 2001;18:743–756. [PubMed]
  • Mills CD, Johnson KM, Hulsebosch CE. Group I metabotropic glutamate receptors in spinal cord injury: Roles in neuroprotection and the development of chronic central pain. J Neurotrauma. 2002;19:23–42. [PubMed]
  • Nesic O, Lee J, Johnson KM, Ye Z, Xu GY, Unabia GC, Wood TG, McAdoo DJ, Westlund KH, Hulsebosch CE, Perez-Polo JR. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J Neurochem. 2005;95:998–1014. [PubMed]
  • Nesic O, Svrakic NM, Xu GY, McAdoo D, Westlund KN, Hulsebosch CE, Ye Z, Galante A, Soteropoulos P, Tolias P, Young W, Hart RP, Perez-Polo JR. DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition. J Neurosci Res. 2002;68:406–423. [PubMed]
  • Piani D, Spranger M, Frei K, Schaffner A, Fontana A. Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive intermediates and cytokines. Eur J Immunol. 1992;22:2429–2439. [PubMed]
  • Popovich PG, Wei P, Stokes BT. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol. 1997;377:443–464. [PubMed]
  • Rafati DS, Geissler K, Johnson K, Unabia G, Hulsebosch C, Nesic-Taylor O, Perez-Polo JR. Nuclear factor-kappaB decoy amelioration of spinal cord injury-induced inflammation and behavior outcomes. J Neurosci Res. 2008;15:566–580. [PubMed]
  • 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]
  • Rooney BA, Crown ED, Hulsebosch CE, McAdoo DJ. Preemptive analgesia with lidocaine prevents failed back surgery syndrome. Exp Neurol. 2007;204:589–596. [PubMed]
  • Shafer RA, Murphy S. Activated astrocytes induce nitric oxide synthase-2 in cerebral endothelium via tumor necrosis factor alpha. Glia. 1997;21:370–379. [PubMed]
  • Siddall PJ, Yezierski RP, Loeser JD. Taxonomy and epidemiology of spinal cord injury pain. In: Yeziersk RP, Burchiel KJ, editors. Spinal Cord Injury Pain: Assessment, Mechanisms, Management Progress in Pain Research and Management. Vol. 23. IASP Press; Seattle: 2002. pp. 9–24.
  • Sjolund BH. Pain and rehabilitation after spinal cord injury: the case of sensory spasticity? Brain Res Brain Res Rev. 2002;40:250–256. [PubMed]
  • Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY, Yaksh TL. Spinal p38β isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem. 2005a;92:1508–1520. [PubMed]
  • Svensson CI, Schäfers M, Jones TL, Powell H, Sorkin LS. Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett. 2005b;379:209–213. [PubMed]
  • Tanaka M, Sotomatsu A, Yoshida T, Hirai S, Nishida A. Detection of superoxide production by activated microglia using a sensitive and specific chemiluminescence assay and microglia-mediated PC12h cell death. J Neurochem. 1994;63:266–270. [PubMed]
  • Tasker RR, Dostrovsky JO. Deafferentation and central pain. In: Wall PD, Melzack R, editors. Textbook of Pain. 2nd. Churchill Livingstone; New York: 1989. pp. 154–180.
  • Tawfik VL, Nutile-McMenemy N, LaCroix-Fralish ML, DeLeo JA. Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immunity. 2007;21:238–246. [PubMed]
  • Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi Y, 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]
  • Vierck CJ, Jr, Siddall P, Yezierski RP. Pain following spinal cord injury: Animal models and mechanistic studies. Pain. 2000;89:1–5. [PubMed]
  • Villegas J. Axon-Schwann cell interaction in the squid nerve fibre. J Physiol. 1972;225:275–296. [PubMed]
  • Xu GY, Liu S, Hughes MG, McAdoo DJ. Glutamate-induced losses of oligodendrocytes and neurons and activation of caspase-3 in the rat spinal cord. Neuroscience. 2008;153:1034–1047. [PMC free article] [PubMed]
  • Xu XJ, Hao JX, Aldskogius H, Seiger A, Wiesenfeld-Hallin Z. Chronic pain-related syndrome in rats after ischemic spinal cord lesion: a possible animal model for pain in patients with spinal cord injury. Pain. 1992;48:279–290. [PubMed]
  • Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL. Excitotoxic spinal cord injury – behavioral and morphological characteristics of a central pain model. Pain. 1998;75:141–155. [PubMed]
  • 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]