The role of neuroinflammation and neuroimmune activation in ... : PAIN (original) (raw)
1. Introduction
Interest in neuroinflammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system (CNS) inflammation and immune responses in the etiology of neurological disorders such as AIDS-associated dementia and pain, Alzheimer's disease, stroke, Parkinson's disease, traumatic brain and spinal cord injury, and demyelinating diseases such as multiple sclerosis (Ruffolo et al., 1999). One approach to the treatment of these conditions is the implementation of putative anti-inflammatory and/or immunosuppressant strategies, which includes the use of methylprednisolone or steroids without glucocorticoid properties (the 21 aminosteroids), and synthetic glycolipid GM-1 gangliosides that ultimately result in the protection or rescuing of neurons in the penumbral region of a pathological insult. These neuroprotective strategies (with anti-inflammatory or immunosuppressant components) are presently being used to treat acute and chronic neurological diseases including: stroke, subarachnoid hemorrhage, brain and spinal cord injury, hypoxic-ischemic encephalopathy, Parkinson's, Alzheimer's and Huntington's disease, amyotropic lateral sclerosis, and diabetic and toxic neuropathies (Wood, 2000). Since some of these conditions are also associated with persistent pain states, it is possible that there is a connection between the neurodegenerative characteristics of these central disorders and the mechanisms responsible for chronic pain.
An important first step in understanding the role of neuroinflammation and neuroimmune activation in persistent pain is to clarify terminology. Immunity, the state of protection from infectious disease and injury, is characterized by nonspecific (innate) and specific (adaptive) components. Innate immunity can be envisioned to include four types of defensive barriers: anatomic, physiologic, phagocytic and inflammatory. The hallmark of the inflammatory component of this innate immune response is the infiltration and/or migration of cells to the site of injury. Therefore, neuroinflammation can be defined as the infiltration of immune cells into the site of injury in response to damage of the peripheral or central nervous system. Unlike innate immunity, adaptive immunity displays specificity, diversity, memory and self/nonself recognition. These two immunological responses have an important interactive relationship. For example, perivascular macrophages, one of the first cells to respond in innate immunity are intimately involved in precipitating the specific, adaptive immune response that involves lymphocytes and antigen-presenting cells. Broadly defined, neuroimmune activation involves endothelial cells, microglia and astrocytes. Activation of these cells leads to subsequent production of cytokines, chemokines, and the expression of surface antigens (to be further discussed) that enhance the immune cascade without infiltration of immune cells to the site of injury and robust pathological sequelae.
In light of the enormous interest in the etiology of CNS disorders, it is not surprising that the potential involvement of neuroinflammation and neuroimmune activation has been considered to play a role in the development of acute and chronic pain (Watkins and Maier, 1999). In the case of persistent pain states, mounting evidence has shown that both neuroinflammation and neuroimmune activation occur following peripheral and central injury. We will review this burgeoning area of research by highlighting recent advances with a focus on immune cells and immune mediators at peripheral and central sites of injury, and the potential modulation of this complex inflammatory/immune response as a novel therapy for the treatment of persistent pain.
2. Immune cells and mediators of CNS disease
The majority of recent pain research related to the arena of neuroimmune function has focused, perhaps naively, on the involvement of cytokines and growth factors (DeLeo et al., 1996; Woolf et al., 1997). When the complex interactions of the immune cascade are realized, this reductionist approach limits the potential to delineate the comprehensive role of neuroinflammation and neuroimmune activation in the generation and/or maintenance of chronic pain. Immune cells and a variety of additional immune mediators should not be ignored in the context of the dynamic interaction that occurs following injury to the nervous system. How these cells/mediators synergize to affect neuronal function and survivability is of critical importance to understanding the contribution of inflammation and immune responses to the evolution of chronic pain states.
2.1. Microglia: macrophages of the CNS
Glial cells (microglia, astrocytes, and oligodendrocytes) constitute over 70% of the total cell population in the brain and spinal cord. Once thought of as merely a physical support system for neurons, glia have recently come under intense investigation as key neuromodulatory, neurotrophic and neuroimmune elements in the CNS. In the peripheral nerve system, an acute inflammatory response is initiated by an influx of macrophages (representing the innate immune component of the response). Activation of monocytes leads to the release of chemokines that are needed to recruit other immune cells. Microglia, cells of monocytic origin, are the macrophages of the CNS and as such perform a vast number of immune-related duties (Hickey and Kimura, 1988). Together with astrocytes, microglial form a regularly spaced network of resident glial cells with microglial representing the antigen-presenting cells of the CNS. Although it is not known whether glia are the first responders to injury or respond to an ‘emergency signal’ from neurons, the fact remains that microglia present one of the first noticeable immune responses to several types of peripheral nerve or CNS injury (Kreutzberg, 1996). Although the initial signal for microglial activation is not well understood, neuronal depolarization following injury combined with extracellular ion changes (especially potassium), metabolic perturbations and changes in ion and acid-base balances in the microenvironment may be the major stimuli (Caggiano and Kraig, 1996).
Microglia have been described as performing ‘surveillance’ and ‘housekeeping’ duties in concert with an array of inactivating and cytoprotective mechanisms which buffer these activities. Events which compromise this normal homeostatic balance thereby resulting in cellular dysfunction and/or cell death. With the persistence of a perturbing event, such as injury, the self-regulatory properties of the glial response system are no longer capable of adequately maintaining the normal biochemical milieu. The result is the triggering of a cascade of biochemical and molecular events encompassing those attributed to excitotoxic and inflammatory cascades. In the case of spinal cord injury these events include the release of glutamate, elevation of intracellular calcium, activation of transcription factors (NF-κB), and the upregulation of synthetic pathways for cytokines, chemokines and adhesion molecules. These events are similar to those associated with peripheral nerve and/or tissue damage (Dubner 1997).
Central and peripheral injuries per se are not the only events capable of initiating these multifaceted cascades of cellular events. Any systemic perturbation causing the disruption of normal homeostatic processes can be viewed as capable of producing a central neural response that is exquisitely monitored by supporting glial cells. At some point the self-regulating properties of microglia break down and with this is a transition in function from general ‘housekeeping’ to an exaggerated state of ‘protect and rescue,’ and ultimately to a state of ‘house-cleaning and repair’. In the event of prolonged activation of microglia as may be found in a chronic state of injury or disease, there is the possibility of ‘bystander lysis’ which results in the gradual progression of cellular dysfunction and death.
Glia are indeed intimately involved in the neuroimmune response following peripheral nerve or central injury that results in persistent pain. However, the concept that all glia are producing the same deleterious proteins and that ameliorating their function will have a beneficial outcome for persistent pain may be naÏve. The use of OX-42, an antibody that labels CR3/CD11b on microglia, is an excellent, sensitive marker of CNS trauma. However, it is not a specific marker for either trauma or nociception (Colburn et al., 1997; Sweitzer et al., 1999). Using immunocytochemistry, it has been demonstrated that only a subpopulation of microglia express specific surface antigens such as major histocompatibility complex (MHC) II and CD4+ expression in response to peripheral nerve injury that results in persistent neuropathic pain (DeLeo et al., 2000).
2.2. Cytokines: neuromodulators of the CNS
Cytokines and growth factors have been strongly implicated in the generation of pathological pain states at both peripheral and central nervous system sites (Clatworthy et al., 1995; Sommer et al., 1998; Woolf et al., 1997; Laughlin et al., 2000). Cytokines are regulatory proteins whose pleiotropic actions modulate the inflammatory response of all cells of the immune system. They regulate both the amplitude and duration of the immune response. They can be broadly classified into four major groups: Growth Factors, Interleukins, Interferons, and Tumor Necrosis Factor. Over the past 3 years, an explosion of research in the neurobiology of cytokines has supported the role of cytokines as neuromodulators in the CNS (Vitkovic et al., 2000). Recently, there have been numerous studies exploring the consequences of cytokine injection into the CNS and local application of cytokines on peripheral nerves and nerve roots (e.g. DeLeo et al., 1996; Wagner and Myers, 1996). Unfortunately, the physiological and pathological relevance of these studies to in vivo neuroinflammation and neuroimmune activation is not known.
The concept that cytokine expression may be beneficial and/or deleterious is illustrated by the potential dichotomous role of the immune response in stroke, multiple sclerosis, CNS regeneration, and even pain generation. For example, the immune system may be protective and even assist with the process of regeneration. Alternatively, the immune system if unchecked, may also exacerbate damage in the process of eliminating dying tissue. This dichotomy is illustrated by the findings that some cytokines are involved in immune-mediated repair of the contused spinal cord and axotomized facial nucleus (Streit et al., 1998). On the other hand, depletion of peripheral macrophages and hence their proinflammatory cytokine products, results in increased neuronal sprouting following spinal cord injury (Popovich et al., 1999). Using this same peripheral macrophage depletion method, nerve injury-induced mechanical allodynia was unaltered suggesting a limited local role of peripheral macrophages in the production of behavioral sensitivity (Rutkowski et al., 2000). The cytokine and neuroimmune dualism is also exemplified in studies demonstrating that IL-1β is pronociceptive, and yet, in contrast, has the ability to reduce inflammatory nociception in the carrageenan model (Watkins et al., 1995; Souter and Garry, 2000). Therefore, further research is warranted to fully understand the role of cytokines in the pathophysiology of persistent pain states.
The chemotactic cytokines, chemokines, along with cellular adhesion molecules play a major role in leukocyte reorientation and migration in response to chemical stimuli. Chemokine classification is based upon the presence and position of conserved cysteine residues. C–X–C or alpha chemokines function primarily as neutrophil and lymphocyte chemoattractants and prototypical family members include IL-8, MIP-2, KC, IP-10, and MIG. C–C or beta chemokines are chemotactic for monocytes and T cells and include such members as MIP-1α, β MCPs 1–5, eotaxin, and RANTES. Chemokines play an important role in recruiting cells into areas of active inflammation. In fact, it has been proposed that selective chemokine expression by CNS cells is crucial for post-traumatic leukocyte accumulation (Ransohoff and Tani, 1998).
Chemokines are synthesized locally at sites of inflammation and establish a concentration gradient to which target cell populations migrate. Several studies have examined the expression of chemokines in response to CNS insults such as experimental autoimmune encephalomyelitis (Glabinski et al., 1997). This chemokine response is critical in the neuroinflammatory response to peripheral nerve injury that results in painful neuropathy since there is evidence that T-cells infiltrate into the CNS after L5 spinal nerve transection (Sweitzer et al., 2000). These data demonstrate that following a focal peripheral nerve injury there is a selective alteration in the blood–brain barrier integrity at the level of the lumbar spinal cord. Similarly, alterations in the tight junctions of the blood–brain barrier are also induced by peripheral inflammatory pain states (Huber et al., 2000). Understanding the nature of peripheral and CNS chemokine interactions during the course of neuropathy may identify the cell types that play an active role in the recruitment of immune cells after injury and the subsequent establishment and progression of persistent pain.
The association of the above neuroimmune cascade with spinal sensitization, the potential pathological correlate to persistent pain states, can be found in the mounting evidence that cytokines induce the release or expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and substance P as well as enhancing capsaicin sensitivity (e.g. Nicol et al., 1997). Similarly, activated glial cells synthesize proinflammatory cytokines, proteases, NO, glutamate, superoxide anions, hydrogen peroxide, eicosanoids and other toxins that act by way of the _N_-methyl-D-aspartate (NMDA) receptors. The production of arachidonic acid potentially exacerbates the injury process by increasing extracellular levels of aspartate and glutamate by inhibiting sodium-dependent uptake and by stimulating exocytosis of glutamate in synergy with PKC activation. Activation of the amino acid cascade also leads to the synthesis of eicosanoids which regulate neuronal ion channels and the formation of superoxide free radicals. Therefore, cytokines have the capacity to create downstream modulation of cell signaling events and at the extreme cell death. Such changes in the CNS milieu can have a direct effect on spinal sensitization.
In recent years the nuclear transcription factor NF-κB has been thought of as the ‘central switch’ or ‘central mediator of the immune response’ controlling the synthesis of different cytokines and chemokines, MHC molecules, proteins involved in antigen presentation, receptors required for neutrophil adhesion and migration across blood vessels (Wood, 2000). NF-κB is activated by more than 150 stimuli and results in the induction of more than 150 genes which influence cell survival and maintenance of normal functional integrity (Pahl, 1999). Genes regulated by NF-κB include enzymes for COX-2, iNOS and prostaglandin synthase-2, interleukin-6 and -1β, dynorphin, and intercellular and vascular adhesion molecules. It is interesting to note that aspirin and glucocorticoids, effective analgesic and anti-inflammatory agents, inhibit NF-κB (Jue et al., 1999). In addition, it has been shown that an NF-κB inhibitor reduced the induction of dynorphin-induced allodynia (Laughlin et al., 2000).
3. Peripheral immune response to nerve injury
Tissue injury or infection gives rise to an acute inflammatory response or in immunological terms, the innate (nonspecific) immunity described earlier. This process is the first step in the immune response that is seminal for host defense as well as tissue repair. There is a substantial body of literature that indicates a florid neuroinflammatory reaction at the site of nerve injury that manifests in behaviors suggestive of neuropathic pain. For example, immune cell infiltration at the nerve injury site and increased endoneural levels of proinflammatory cytokines have been demonstrated in a rodent model of neuropathy (Wagner and Myers, 1996). Additionally, local immunosuppression at the site of nerve injury using corticosteroids, thalidomide or the anti-inflammatory cytokine, IL-10, has been found to attenuate neuropathic pain behaviors following nerve injury in rodents (Johansson and Bennett, 1997; Sommer et al., 1998; Wagner et al., 1998).
An experimental neuritis of the rat sciatic nerve provokes a local immune reaction characterized by endoneural infiltration of granulocytes and CD4 and CD8 T-lymphocytes (Eliav et al., 1999). This reaction, even without significant axonal damage, is not surprising in light of the predicted immune response due to a local inflammatory stimulus following exposure of carrageenan or complete Freund's adjuvant. These findings lend support for a distinct neuroinflammatory event without significant nerve injury in the generation of persistent neuropathic pain.
4. Central immune response to injury
The CNS has long been considered an immunologically privileged site, a place wherein the immune system performed few functions. Over the past decade, this view has altered dramatically. The CNS is actively involved in immunological phenomena that are both physiological and pathological. Work in various laboratories has focused on mechanisms by which neuroinflammation and neuroimmune activation develop in the CNS in response to peripheral nerve or tissue injury, central root or spinal injury, or administration of LPS and the HIV envelope protein, gp120, and how this relates to the development of both acute and persistent pain (Watkins and Maier, 1999). Toward this end, rodent models of neuropathy, radiculopathy and spinal cord injury have been utilized. In the dissection of these immunologically distinct systems research has focused on glial activation, cell migration and trafficking, adhesion molecule expression, antigen presentation and cytokine production (Colburn et al., 1997; Laughlin et al., 2000; Sweitzer et al., 2000).
An example of the central inflammatory response to injury is seen in the events following spinal cord injury which results in subsequent persistent pain states. Activation of NF-κB, increased expression of mRNAs for TNF, IL-1β, COX-2, and iNOS are observed following traumatic and/or excitotoxic-induced injury (Bethea et al., 1998; Plunkett et al., 2000). In concert with these biochemical and molecular events, is the reaction of microglia and astrocytes and the invasion of blood-borne macrophages to the site of injury. Inhibition of the inflammatory or immune response with the exogenous application of the anti-inflammatory cytokine IL-10 or the immunosuppressant cyclosporin A in the excitotoxic model of spinal cord injury results in a significant reduction in the extent of tissue damage (Yu et al., 2000). While there are many potential actions of IL-10 and cyclosporin A, the putative neuroprotective effects of these agents along with the IL-10-induced decrease in mRNA expression for proinflammatory cytokines and iNOS may be important factors responsible for the effects of these agents on the initiation of pain behavior following excitotoxic injury (Plunkett et al., 2000; Yu et al., 2000).
5. Conclusions and future directions
There remain many unanswered questions concerning the interaction and significance of different events associated with the activation of immune and inflammatory cascades, and most importantly the impact of these events on the structural and functional integrity of CNS neurons. Although the microglial reaction to injury and the release of cytokines represent symbolic events reflective of ongoing immune/inflammatory processes, one must not ignore the many other consequences of inflammation that can have a severe impact (acute and chronic) on the excitability and survivability of central neurons. Some of these include: breakdown of the blood–brain barrier, production of reactive oxygen species, eicosanoids, cellular adhesion molecule upregulation, migration of antigen-specific B- and T-lymphocytes and monocytes, infiltration of neutrophils; and constriction of cerebral arteries. Furthermore, there are also signaling molecules like substance P that stimulate the proliferation and differentiation of lymphocytes and induce immunoglobulin synthesis; calcineurin (a calcium-dependent phosphatase) which dephosphorylates NOS, and β-amyloid which activates microglial via a positive feedback loop involving astrocytes. These signaling molecules are all part of the inflammatory response to pathological conditions. The action of these molecules can potentially lead to cellular dysfunction and expression of clinical symptoms, including chronic pain.
Two additional potential mediators in the evolution of chronic pain states that play a role in neuroinflammation are the ‘complement system’ and ATP. The complement system, which is part of the innate branch of the immune system, provides the impetus for an immediate inflammatory response. Increased expression of complement mRNA follows CNS injury and complement proteins are thought to be involved in synaptic remodeling as well as catastrophic neurodegenerative consequences. The role of complement in persistent pain states or as a potential therapeutic target for the treatment of chronic pain is as yet unknown, although inhibition of complement in animal models of myasthenia gravis, and multiple sclerosis ameliorates disease progression (Spiegel et al., 1998). Additionally, damaged neurons release ATP which in turn activates microglial purinoreceptors. ATP induces release of IL-1β and stimulates an increase of intracellular calcium leading to the release of plasminogen. Plasminogen enhances synaptic transmission via NMDA receptors. Although it is beyond the scope of this review to discuss the potential role of all of these events and signaling molecules in the emergence of persistent pain states, it is clear that this will be an exciting and hopefully fruitful area of research for many years.
In summary, the cells and molecules involved in the immune/inflammatory process act together in an exquisitely adaptable network whose complexity rivals that of the CNS. Recognizing this, it becomes obvious that the nervous system must orchestrate a dynamic immune response to stressors and injury. However, as the understanding of neuroinflammation and neuroimmune activation unfolds, it is becoming more apparent that the nature and number of cellular mediators of inflammation are quite distinct in CNS tissue compared with the periphery (Ruffolo et al., 1999). As we elucidate the tight regulatory mechanisms responsible for the induction of neuroinflammation and neuroimmune activation in the CNS, we will begin to appreciate the balance between inflammation/immune-induced tissue repair and damage and how these processes relate to neuronal function/dysfunction. The opportunities for pharmacological intervention targeting the neuroinflammatory and neuroimmune components of various pathological conditions encompass, but are by no means limited to, immunosuppression within the CNS, specific immune mediator inhibitors or potentiators, as well as glial modulating agents. We also must recognize the dynamic interplay between the hypothalamic-pituitary–adrenal (HPA) axis, stress, and neuroimmune function as it relates to the development and maintenance of chronic pain states. Knowledge gained from research in these areas may ultimately expand the possibilities of novel pharmacopeia for the prevention and treatment of chronic pain states;
‘The universe is full of magical things patiently waiting for our wits to grow sharper’
Eden Phillpotts, 1862–1960
References
Bethea JR, Castro MC, Lee TT, Dietrich WD, Yezierski RP. Traumatic spinal cord injury induces nuclear factor kappa-B activation. J Neurosci. 1998;18:3251-3260.
Caggiano AO, Kraig RP. Eicosanoids and nitric oxide influence induction of reactive gliosis from spreading depression in microglia but not astrocytes. J Comp Neurol. 1996;369:93-108.
Clatworthy AL, Illich PA, Castro GA, Walters ET. Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain. Neurosci Lett. 1995;5-8.
Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol. 1997;79:163-175.
DeLeo JA, Colburn RW, Nichols M, Malhotra A. Interleukin (IL)-6 mediated hyperalgesia/allodynia and increased spinal IL-6 in a rat mononeuropathy model. J Interferon Cytokine Res. 1996;16:695-700.
DeLeo JA, Arruda J, Rutkowski M, Sweitzer S, Winkelstein BA, Wynkoop T. Differential physiological and pharmacological neuroimmune outcomes in rat models of neuropathic and radicular pain. Soc Neurosci Abstr. 2000;733:1.
Dubner R., 1997. Neural basis of persistent pain: sensory specialization, sensory modulation, and neuronal plasticity. In: Turner JA, Jensen TS, Wiesenfield-Hallin Z, editors., Proceedings of the 8th world congress on pain, IASP, Seattle, WA.
Eliav E, Herzberg U, Uda MA, Bennett G. Neuropathic pain from an experimental neuritis of the rat sciatic nerve. Pain. 1999;83:169-182.
Glabinski A, Tani M, Strieter R, Tuohy V, Ransohoff R. Synchronous synthesis of α and β chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol. 1997;150:617-630.
Hickey WF, Kimura H. Perivascular microglia are bone marrow derived and present antigen in vivo. Science. 1988;239:290-292.
Huber JD, Witt KA, Hom S, Egleton RD, Davis TP. Blood–brain barrier tight junction alteration induced by peripheral inflammatory pain. Soc Neurosci Abstr. 2000;26:650.
Johansson A, Bennett GJ. The effect of local methylprednisolone on pain in a nerve injury model – a pilot study. Reg Anesth. 1997;22:59-65.
Jue DM, Jeon KI, Jeong JY. Nuclear factor kappa B pathway as a therapeutic target in rheumatoid arthritis. J Korean Med Sci. 1999;14:231-238.
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312-318.
Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL. Involvement of the proinflammatory cytokine IL-1β in dynorphin-induced allodynia. Pain. 2000;84:159-167.
Nicol GD, Lopshire JC, Pafford CM. Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons. J Neurosci. 1997;17:975-982.
Pahl HL. Activators and target genes of Rel/NF-κB transcription factors. Oncogene. 1999;18:6853-6866.
Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP. Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2000. in press.
Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 1999;158:351-365.
Ransohoff R, Tani M. Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci. 1998;21:154-159.
Ruffolo R, Fuerstein GZ, Hunter AJ, Poste G, Metcalf BW. Inflammatory cells and mediators in CNS diseases. Netherlands: Harwood Academic; 1999.
Rutkowski M, Arruda J, Sweitzer S, DeLeo JA. The limited role of peripheral macrophages in the generation of neuropathic pain behavior in a rat model of neuropathy. Pharmacol Behav. 2000;71:225-235.
Sommer C, Marziniak M, Myers RR. The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain. 1998;74:83-91.
Souter AJ, Garry MG. Spinal interleukin-1β reduces inflammatory pain. Pain. 2000;86:63-68.
Spiegel K, Emmerling MR, Barnum SR., 1998. Strategies for inhibition of complement activation in the treatment of neurodegenerative diseases. In: Wood PL, editor., Neuroinflammation: mechanisms and management. Humana, Totowa, pp. 129-176.
Streit WJ, Semple-Rowland SL, Hurley SD, Miller RC, Popovich PG, Stokes BT. Cytokine mRNA profiles in contused spinal cord and axotomized facial nucleus suggest a beneficial role for inflammation and gliosis. Exp Neurol. 1998;152:74-87.
Sweitzer S, Colburn RW, Rutkowski M, DeLeo JA. Acute peripheral inflammation induces moderate glial activation and spinal IL-1β expression that correlates with pain behavior in the rat. Brain Res. 1999;829:209-221.
Sweitzer S, Pahl J, Hickey WF, DeLeo JA. Focal nerve injury induces immune cell trafficking into the CNS: relationship to neuropathic pain. J Immunol submitted.
Vitkovic L, Bockaert J, Jacque C. ‘Inflammatory’ cytokine: neuromodulators in normal brain? J Neurochem. 2000;74:457-471.
Wagner R, Myers RR. Endoneurial injection of TNF-α produces neuropathic pain behaviors. Neuroreport. 1996;7:2897-2901.
Wagner R, Janjigian M, Myers RR. Anti-inflammatory interleukin-10 therapy in CCI neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNFα expression. Pain. 1998;74:35-42.
Watkins L, Maier SF. Cytokines and pain: progress in inflammation research. Boston, MA: Birkhauser; 1999.
Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain. 1995;63:289-302.
Wood PL. Neuroinflammation: mechanisms and management. Totowa: Humana; 2000.
Woolf CJ, Allchome A, Safieh-Garabedian B, Poole S. Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumor necrosis factor α. Br J Pharmacol. 1997;121:417-424.
Yu CG, Bethea JR, Fairbanks CA, Wilcox GL, Yezierski RP. Effects of cyclosporin, interleukin-10 and agmatine on a spontaneous pain-like behavior following excitotoxic spinal cord injury in the rat. Soc Neurosci Abstr. 2000;733.8.
© 2001 Lippincott Williams & Wilkins, Inc.