Robert P. Yezierski

The role of neuroinflammation and neuroimmune activation in persistent pain.

Interest in neuroin ̄ammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system (CNS) in ̄ammation and immune responses in the etiology of neurological disorders such as AIDS-associated dementia and pain, Alzheimers disease, stroke, Parkinsons 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-in ̄ammatory 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-in ̄ammatory 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, Parkinsons, Alzheimers and Huntingtons 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 ®rst step in understanding the role of neuroin ̄ammation and neuroimmune activation in persistent pain is to clarify terminology. Immunity, the state of protection from infectious disease and injury, is characterized by nonspeci®c (innate) and speci®c (adaptive) components. Innate immunity can be envisioned to include four types of defensive barriers: anatomic, physiologic, phagocytic and in ̄ammatory. The hallmark of the in ̄ammatory component of this innate immune response is the in®ltration and/or migration of cells to the site of injury. Therefore, neuroin ̄ammation can be de®ned as the in®ltration 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 speci®city, diversity, memory and self/nonself recognition. These two immunological responses have an important interactive relationship. For example, perivascular macrophages, one of the ®rst cells to respond in innate immunity are intimately involved in precipitating the speci®c, adaptive immune response that involves lymphocytes and antigen-presenting cells. Broadly de®ned, 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 in®ltration 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 neuroin ̄ammation 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 neuroin ̄ammation 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 in ̄ammatory/immune response as a novel therapy for the treatment of persistent pain. Pain 90 (2001) 1±6

Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model

&NA; Intraspinal injections of the AMPA‐metabotropic receptor agonist quisqualic acid (QUIS) were made in an effort to simulate injury induced elevations of excitatory amino acids (EAAs), a well documented neurochemical change following spinal cord injury (SCI). The progressive pathological sequela associated with QUIS injections closely resembles the cascade of events described following ischemic and traumatic SCI and the pathogenesis of cavities in the clinical condition of post‐traumatic syringomyelia. Using different injection parameters, i.e. depth and volume, to deliver QUIS into the cord the results have shown that the technique of intraspinal injection can be used to produce graded patterns of neuronal loss in specific regions of the spinal gray matter. Furthermore, neuronal loss in the dorsal horn, sparing the superficial laminae, results in the onset of spontaneous (excessive grooming behavior) and evoked (mechanical allodynia and thermal hyperalgesia) behaviors commonly associated with experimental models of chronic neuropathic pain. Thus, the present results provide a morphological correlate of spontaneous and evoked pain related behaviors following excitotoxic SCI. The behavioral characteristics combined with the similarities between QUIS induced injury and the clinical pathology of SCI support the use of the excitotoxic model in studies related to the central mechanism(s) of altered sensation, including pain, following spinal injury.

Perceived difficulty in dealing with consequences of spinal cord injury

OBJECTIVESnTo determine the perceived difficulty in dealing with consequences of spinal cord injury (SCI) and to explore patterns of how these complications are perceived.nnnDESIGNnPostal survey.nnnSETTINGnGeneral community.nnnPARTICIPANTSnIndividuals with traumatic SCI (n = 430).nnnMETHODSnSubjects (n = 877) were selected from The Miami Project database and were sent a questionnaire in which they were asked to rate their difficulty in dealing with 10 consequences of SCI, on a scale ranging from 0 (not hard at all) to 10 (extremely hard).nnnRESULTSnThe questionnaire was returned by 430 individuals (49%). Five consequences (decreased ability to walk or move, decreased control of bowel, decreased control of bladder, decreased sexual function, and pain) were rated highest (means, 8.2 to 6.2). High ratings of feeling sad were associated with high ratings of most other consequences, and a cluster analysis revealed interrelationships between the ways the various consequences were perceived.nnnCONCLUSIONSnSeveral consequences of SCI are frequently perceived as being very difficult to deal with. Sadness may influence how well a person deals with other consequences of SCI. The observed patterns in perceived difficulty dealing with complications of SCI need to be explored further because they are important in our understanding and treatment of the medical conditions that may follow SCI.

Pain following spinal cord injury: the clinical problem and experimental studies.

&NA; The problem of pain following spinal cord injury challenges the health care community to develop new treatment strategies for patients requiring pain management. A number of pain syndromes are associated with spinal injury based on the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes. Efforts to identify specific characteristics of each syndrome are an important beginning to the successful diagnosis and treatment of spinal injury pain. Without research directed towards understanding the basic mechanisms of this condition, it is likely that the treatment of these patients will remain basically the same as for any other type of pain. In recent years optimism for the development of more effective treatments for central pain of spinal origin has resulted from efforts directed towards understanding the morphological, neurochemical, and physiological responses to spinal injury. Through the use of different experimental models valuable insights related to the mechanism(s) responsible for the onset of central pain following injury have been obtained. At present there are three hypothesis related to this condition: (a) imbalance of sensory channels; (b) loss of spinal inhibitory tone; and (c) the existence of central pattern generators. Future research related to these hypotheses will need to focus on the use of appropriate injury models that simulate the pathological changes associated with human injuries and which lead to clinically relevant pain‐related behaviors. Continued research directed towards an examination of these proposed mechanisms will also require new research strategies and a cooperative working relationship between basic and clinical scientists. In this review the clinical characteristics of spinal injury pain and the results of experimental studies are discussed.

Cytokine involvement in dynorphin-induced allodynia

Abstract Dynorphin A is an endogenous opioid peptide, which has previously been shown to produce a long‐lasting allodynia and hyperalgesia in mice, behavioral states consistent with signs of clinically observed neuropathic pain. This dynorphin‐induced allodynia was used as a pharmacological, central model of neuropathic pain. In this study, we examined the involvement of the cytokine IL‐1&bgr;, the transcription factor nuclear factor kappa B (NF‐&kgr;B), and de novo protein synthesis in the development of allodynia induced by intrathecal (i.t.) administration of dynorphin in male ICR mice. Pretreatment with the protein synthesis inhibitor cycloheximide (0.3–85 nmol), the NF‐&kgr;B inhibitor pyrrolidinedithiocarbamate (PDTC) (0.001–1000 pmol), the IL‐1 receptor antagonist (IL‐1ra) protein (0.01–100 ng), the caspase‐1 inhibitor (YVAD) (0.1–300 pmol), and the anti‐inflammatory cytokine IL‐10 (0.1–300 ng) all dose‐dependently reduced the induction of dynorphin‐induced allodynia. Finally, IL‐10 administered within the first 24 h after the dynorphin insult prevented the development of chronic allodynia. These results demonstrate that the anti‐inflammatory cytokines IL‐10 and IL‐1ra impede the development of dynorphin‐induced allodynia. These results also suggest that production of new proteins through NF‐&kgr;B activation is required for the induction of allodynia. We speculate that IL‐1ra, IL‐10, PDTC and cycloheximide interfere with the central pro‐inflammatory cascade. Modulation of cytokine activity in the spinal cord may therefore prove to be an effective therapeutic strategy for the treatment of chronic pain.

Neuroprotective Effects of Interleukin-10 Following Excitotoxic Spinal Cord Injury

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Inflammatory responses appear to be a major component of the secondary neuronal injury initiated by SCI and play a role in the pathogenesis of QUIS-induced injury. IL-10 is a potent antiinflammatory cytokine that has been shown to reduce inflammation and improve functional outcome in human and animal models of inflammatory diseases. We propose the administration of IL-10 following excitotoxic SCI will attenuate the inflammatory response, thus resulting in increased neuronal survival. Female, Sprague-Dawley rats were given intraspinal injections of QUIS followed by either intraspinal (5 ng, n = 8) or systemic injections (5 microgram n = 14) of IL-10. Survival times were varied (2-3 days) in order to produce a range of injury states and inflammatory involvement. When administered intraspinally, IL-10 significantly exacerbated the QUIS damage (P < 0.05), resulting in an 11.2% increase in lesion volume. When given systemically, IL-10 significantly decreased lesion volume by 18.1% in the more advanced injury (P < 0.05), but did not effect the more acute injury. These divergent effects were attributed to the modest inflammatory response in the short-term injury compared to the more robust inflammatory response in the more chronic injury. In conclusion, reducing the inflammatory response to SCI by systemic administration of IL-10 resulted in a significant reduction in neuronal damage, suggesting that targeting injury-induced inflammation may be an effective treatment strategy for acute SCI.

The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat

The mechanoreceptive properties of rat spinal sensory neurons were evaluated in segments adjacent to those injected with the excitatory amino acid agonist quisqualic acid. Following survival periods of 7-36 days cells recorded in quisqualate injected animals had an increased level of background activity, increased sensitivity to mechanical stimuli, and an increase in the duration of afterdischarge responses. It is suggested that a central mechanism that alters the functional state of neurons may be responsible for the sensory abnormalities, e.g. allodynia and hyperalgesia, that occur following excitotoxic induced cell death associated with ischemic and traumatic spinal cord injury.

Pain following spinal cord injury: pathophysiology and central mechanisms

Publisher Summary This chapter reviews the results of experimental and clinical studies that provide insights into possible mechanism(s) underlying selected pain states following spinal injury. Emphasis is placed on studies related to central dysesthetic pain, perhaps the most disabling of all sensory complications associated with spinal cord injury (SCI). The epidemiological and clinical characteristics of different SCI pain syndromes are reviewed. The most obvious pathological characteristics associated with traumatic or ischemic injury to the spinal cord include but are by no means limited to the dramatic loss of neurons, damage to surrounding white matter, astrocytic scarring, syrinx formation, and breakdown of the spinal blood brain barrier. Common central injury cascade was proposed for the initiation of pain-related behaviors following central or peripheral injury. The different components of this central cascade are shown that include anatomical, neurochemical, excitotoxic, and inflammatory events that collectively interact to influence the functional state of spinal sensory neurons leading to the onset of different clinical pain states. Continued research directed towards specific components of the spinal injury cascade should provide a better understanding of spinal and supraspinal mechanisms responsible for this condition and the future development of novel therapeutic strategies.

Pain following spinal cord injury: animal models and mechanistic studies.

Charles J. Vierck Jr.*, Phillip Siddall, Robert P. Yezierski Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610-0244, USA McNight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610-0244, USA Pain Management and Research Centre, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia The Miami Project, University of Miami, Miami, FL 33136, USA Department of Neurological Surgery, University of Miami, Miami, FL 33136, USA Department of Anatomy and Cell Biology, University of Miami, Miami, FL 33136, USA

NMDA and non-NMDA receptor antagonists protect against excitotoxic injury in the rat spinal cord

The neuroprotective properties of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) and the non-NMDA antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) and alpha-methyl-4-carboxyphenylglycine (MCPG) were evaluated against neuronal injury produced by the intraspinal injection of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). Forty-nine animals were divided into eight groups in order to evaluate the effects of different drug combinations: (a) NMDA; (b) NMDA + MCPG; (c) NMDA + NBQX; (d) NMDA + MK-801; (e) AMPA; (f) AMPA + MCPG; (g) AMPA + MK-801; and (h) AMPA + NBQX. Drugs were microinjected into spinal segments T12-L3 through a micropipette attached to a Hamilton microliter syringe. Spinal cords were evaluated after a survival period of 48 h at which time NMDA and AMPA were found to produce morphological changes over the concentration ranges of 125-500 mM and 75-500 microM, respectively. Neuronal loss following injections of NMDA + MK-801 or AMPA + NBQX was significantly less than that following injections of NMDA or AMPA alone. By contrast, neuronal loss following co-injections of NMDA or AMPA with inappropriate antagonists, i.e., NMDA + NBQX/MCPG or AMPA + MCPG/MK-801, was not significantly different from that produced by NMDA or AMPA. The results suggest that elevations in spinal levels of glutamate followed by prolonged activation of NMDA and AMPA receptor subtypes initiate an excitotoxic cascade resulting in neuronal injury. Blockade of NMDA and AMPA effects by MK-801 and NBQX respectively confirms the well documented neuroprotective effects of these drugs and lends support to the potential importance of NMDA and especially AMPA receptor antagonists as therapeutic agents in the treatment of acute spinal cord injury.