The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration

Following an initial impact after spinal cord injury (SCI), there is a cascade of downstream events termed 'secondary injury', which culminate in progressive degenerative events in the spinal cord. These secondary injury mechanisms include, but are not limited to, ischemia, inflammation, free radical-induced cell death, glutamate excitotoxicity, cytoskeletal degradation and induction of extrinsic and intrinsic apoptotic pathways. There is emerging evidence that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed posttraumatic spinal cord white matter degeneration. Importantly however, the differences in cellular composition and expression of specific types of glutamate receptors in grey versus white matter require a compartmentalized approach to understand the mechanisms of secondary injury after SCI. This review examines mechanisms of secondary white matter injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis. Recent studies have provided new insights into the mechanisms of glutamate release and its potential targets, as well as the downstream pathways associated with glutamate receptor activation in specific types of cells. Evidence from molecular and functional expression of glutamatergic AMPA receptors in white matter glia (and possibly axons), the protective effects of AMPA/kainate antagonists in posttraumatic white matter axonal function, and the vulnerability of oligodendrocytes to excitotoxic cell death suggest that glutamate excitotoxicity is associated with oligodendrocyte apoptosis. The latter mechanism appears key to glutamatergic white matter degeneration after SCI and may represent an attractive therapeutic target.     

Pretreatment with the cyclosporin derivative, NIM811, improves the function of synaptic mitochondria following spinal cord contusion in rats

Trauma to the spinal cord causes a cascade of secondary events, such as mitochondrial dysfunction, which disrupts cellular functions and ultimately leads to cell death. Cyclosporin A (CsA) is a potent immunosuppressant that promotes mitochondrial function by inhibiting mitochondrial permeability transition (mPT). Clinical trials examining CsA in traumatic brain injury are currently under-way, but CsA is potentially neurotoxic. NIM811 is a non-immunosuppressive CsA derivative that inhibits mPT at nanomolar concentrations and with significantly less cytotoxicity than CsA. In the present study, we investigated the effects of NIM811 treatment on mitochondrial bioenergetics and the production of reactive oxygen species following spinal cord injury (SCI) in rats. Rats were pretreated with NIM811 or vehicle, and after 15 min the rats received a "mild/moderate" spinal cord contusion. After 24 h, the spinal cords were rapidly removed and synaptosomal mitochondria were isolated. NIM811 pretreatment significantly improved mitochondrial respiratory control ratios, and the maximal electron transport capacity of complex I and II, as well as their ATP-producing capacity. Consistent with the improvements in mitochondrial function, NIM811 pretreatment significantly decreased free radical production in isolated mitochondria. These studies are the first to demonstrate the therapeutic potential of CsA derivatives in a model of SCI, and support the need for continued investigation of compounds like NIM811 as an acute treatment for human SCI.     

Temporal characterization of mitochondrial bioenergetics after spinal cord injury

Mitochondrial dysfunction following spinal cord injury (SCI) may be critical for the development of secondary pathophysiology and neuronal cell death. Previous studies have demonstrated a loss of mitochondrial bioenergetics at 24 h following SCI. To begin to understand the evolution and study the contribution of mitochondrial dysfunction in pathophysiology of SCI, we investigated mitochondrial bioenergetics in the mid-thoracic region at 6, 12, and 24 h following contusion SCI. It is widely accepted that increased free radical generation plays a critical role in neuronal damage after SCI. Hence, to ascertain the role of free radicals in SCI-induced mitochondrial dysfunction, markers for oxidative damage, including nitrotyrosine (3-NT), lipid peroxidation byproduct (4-hydroxynonenal [HNE]), and protein oxidation (protein carbonyls) were quantified in the same samples of isolated mitochondria during the 24-h time course. The results demonstrate that a significant decline in mitochondrial function begins to occur 12 h post-injury and persists for a least 24 h following SCI. Furthermore, there was a progressive increase in mitochondrial oxidative damage that preceded the loss of mitochondrial bioenergetics, suggesting that free radical damage may be a major mitochondrial secondary injury process. Based on the present results, the temporal profile of mitochondrial dysfunction indicates that interventions targeting mitochondrial oxidative damage and dysfunction may serve as a beneficial pharmacological treatment for acute SCI.     

Pathophysiology and pharmacologic treatment of acute spinal cord injury.

BACKGROUND CONTEXT: The past three decades have witnessed increasing interest in strategies to improve neurologic function after spinal cord injury. As progress is made in our understanding of the pathophysiologic events that occur after acute spinal cord injury, neuroprotective agents are being developed. PURPOSE: Clinicians who treat acute spinal cord injuries should have a basic understanding of the pathophysiologic processes that are initiated after the spinal cord has been injured. A familiarity with the literature on which the current use of methylprednisolone is based is also essential. STUDY DESIGN/SETTING: Literature review. METHODS: Literature review of animal data on pathophysiologic mechanisms, and of both animal and human trials of neuroprotective agents. RESULTS: The mechanical forces imparted to the spinal cord cause primary damage to the neural tissue, but a complex cascade of pathophysiologic processes that imperil adjacent, initially spared tissue to secondary damage rapidly follows this. Attenuating this secondary damage with neuroprotective strategies requires an understanding of these pathophysiologic processes. Many researchers are investigating the role of such processes as ischemia, inflammation, ionic homeostasis and apoptotic cell death in the secondary injury cascade, with hopes of developing specific therapies to diminish their injurious effects. Beyond methylprednisolone, a number of other pharmacologic treatments have been investigated for the acute treatment of spinal cord injury, and even more are on the horizon as potential therapies. CONCLUSIONS: This review summarizes some of the important pathophysiologic processes involved in secondary damage after spinal cord injury and discusses a number of pharmacologic therapies that have either been studied or have future potential for this devastating injury.     

Inflammatory and apoptotic signaling after spinal cord injury

Central nervous system (CNS) destruction in spinal cord injury (SCI) is caused by a complex series of cellular and molecular events. Recent studies have concentrated on signaling by receptors in the tumor necrosis factor receptor (TNFR) superfamily that mediate diverse biological outcomes ranging from inflammation to apoptosis. From the perspective of basic science research, understanding how receptor signaling mediates these divergent responses is critical in clarifying events underlying irreversible cell injury in clinically relevant models of SCI. From a clinical perspective, this work also provides novel targets for the development of therapeutic agents that have the potential to protect the spinal cord from irreversible damage and promote functional recovery. In this review, we discuss how the formation of alternate signaling complexes and receptor membrane localization after SCI can influence life and death decisions of cells stimulated through two members of the TNFR superfamily, Fas/CD95 and TNFR1.     

兔牵张性脊髓损伤的病理形态学改变

为了探索牵张性脊髓损伤的病理机制。我们选用４０只健康日本大耳白兔，随机分成对照组、体感皮层诱发电位波幅下降３０％组，５０％５分钟组、５０％１０分钟组。通过对动物运动功能评价、脊髓组织内丙二醛（ｍａｌｏｎｙｌｏｄｉａｌｄｅｈｙｄｅ，ＭＤＡ）和过氧化物歧化酶（ｓｕｐｅｒｏｘｉｄｅｄｉｓｔｕｍａｓｅ，ＳＯＤ）定量分析、组织形态等方法，研究牵张性脊髓损伤。结果显示：随着撑开负荷增加和作用时间延长。导致脊髓灰白质内血管充盈不足、痉挛直至血管破裂出血。脊髓组织内ＳＯＤ含量下降、ＭＤＡ含量升高。５０％５分钟组和５０％１０分钟组的Ｔａｒｌｏｖ评分障碍率和Ｍｏｌｔ斜板障碍率增大。与对照组相比，其差异有显著性。研究证明脊髓血管的改变是牵张性脊髓损伤的早期病理机制，而自由基介导的脂质过氧化反应则参与了牵张性脊髓损伤的继发性损害过程。     

Effect of the free radical scavenger MCI-186 on spinal cord reperfusion after transient ischemia in the rabbit

Objective: Paraplegia remains a serious complication of aortic operations. The production of free radicals during reperfusion after transient ischemia is believed to induce secondary spinal neuronal injury, resulting in paraplegia. The aim of the present study was to clarify the protective effect and method of administration of antioxidants on the neurological and histological outcome in the animal model for reperfusion injury after transient spinal cord ischemia. Methods: New Zealand white rabbits underwent surgical exposure of the abdominal aorta that was clamped for 15 minutes to achieve spinal cord ischemia. Group A animals received two 10 mg/kg doses of 3-methyl-l-phenyl-2-pyrazolin-5-one (MCI-186) at the time of release of the aortic clamp and 30 minutes later. In group B, MCI-186, 5 mg/kg, was given three times, at the time of aorta clamp release, 30 minutes and 12 hours later. In group C (control group), one dose of vehicle was administered. Neurological status was assessed using modified Tarlov’s score until 168 hours after operation. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. Results: Groups A and B animals had better neurological function than group C (p(0.001). In contrast, group C animals exhibited paraplegia or paraparesis with marked neuronal necrosis. The number of surviving neurons within examined sections of the spinal cord was significantly greater in group B than in group C (p(0.001). Conclusion: In a 15-minute ischemia-reperfusion model using rabbits, systemic repetitious administration of MCI-186, a free radical scavenger, was found to have a protective effect on the spinal cord neurons both neurologically and histologically. We postulate that the drug minimizes the delayed neuronal cell death for reperfusion injury after transient ischemia by reducing the free radical molecules. Moreover, it was thought that we could protect delayed neuronal cell death more effectively by administering MCI-18612 hours later.     

The effects of chronic alpha-tocopherol administration on lipid peroxidation in an experimental model of acute spinal cord injury

Most of the numerous experimental studies to research pathophysiological changes following acute spinal cord injury suggest a two-step mechanism of damage to the spinal cord in which the primary (direct) or mechanical injury caused by the trauma initiates secondary (indirect) or progressive autodestructive injury of the cord. During recent years, free oxygen radical generation and lipid peroxidation have been considered to be responsible for secondary autodestructive injury.Alpha tocopherol occupies an important and unique position in the overall antioxidant defense. Alpha tocopherol-depleted animals are generally more susceptible to the adverse effects of environmental agents than are supplemented animals. This study was planned to study the effectiveness in counteracting this autodestructive process by supplementing alpha-tocopherol in rats maintained on a nutritionally adequate diet, and also to evaluate whether it will provide additional protection or not. Eighty healthy Wistar rats (treatment and controls) were included. The treatment group received 100 mg/kg alpha tocopherol each day, intraperitoneally for seven days. Using a standard acute spinal cord trauma model in Wistar rats trauma was applied, an malondialehyde (MDA) which is a lipid peroxidation product was measured in the traumatized spinal cord at various times following the trauma in order to indirectly evaluate the lipid peroxidation and generation of free oxygen radicals in a time sequence. Statistical analysis of the values demonstrated that malondialdehyde formation in the alpha-tocopherol administered group was significantly lower than in the control group. These findings indicate that longterm administration of alpha-tocopherol may be useful to decrease lipid peroxidation following acute spinal cord trauma.     

Molecular biology of cervical myelopathy and spinal cord injury: role of oligodendrocyte apoptosis

BACKGROUND CONTEXT: Rational design of treatment strategies for cervical myelopathy and spinal cord injury requires a working knowledge of the molecular biology underlying these pathological processes. The cellular process of apoptosis is an important component of tissue and organ development as well as the natural response to disease and injury. Recent studies have convincingly demonstrated that apoptosis also plays a pivotal role in numerous pathological processes, contributing to the adverse effects of various diseases and traumatic conditions. A growing body of evidence has implicated apoptosis as a key determinant of the extent of neurological damage and dysfunction after acute spinal cord injury and in chronic cervical myelopathy. PURPOSE: To provide clinicians and research investigators interested in spinal cord injury and myelopathy with a practical and up-to-date basic science review of cellular apoptosis in the context of spinal cord pathology. STUDY DESIGN/SETTING: A review of recently published or presented data from molecular biological, animal model and human clinical studies. METHODS: A computer-based comprehensive review of the English-language scientific and medical literature was performed in order to identify relevant publications with emphasis given to more recent studies. RESULTS: Investigation into the role of apoptosis in spinal cord injury and myelopathy has drawn the interest of an increasing number of researchers and has yielded a substantial amount of new information. CONCLUSIONS: Apoptosis is a fundamental biological process that contributes to preservation of health as well as development of disease. There is now strong evidence to support a significant role for apoptosis in secondary injury mechanisms after acute spinal cord injury as well in the progressive neurological deficits observed in such conditions as spondylotic cervical myelopathy.     

Disturbances of hydrogen electron transport system and free radical reactions after severe spinal cord injury

Local tissue oxygen consumption, nicotinamide-adenine dinucleotide hydrogenase, coenzyme-Q and alpha-tocopherol were measured and the relationships between damage to the hydrogen electron transport system and free radical reactions were examined in a irreversible rat spinal cord injury model. Damage to the hydrogen electron transport system became apparent in the injured spinal cord segment earlier than expected. Oxygen consumption declined to 26% of the baseline level within five to 30 minutes after injury, by one hour, further declined by 21% and by two hours another 17% and by three to four hours by an additional 13%. This severe disturbance of oxygen metabolism was associated with a marked reduction of adenosine triphosphate. A reduction in coenzyme-Q by 50% was noted within 10 minutes after injury and might be at least partially responsible for these changes since a reduction of coenzyme-Q promotes the semiquinone (.coenzyme-Q) forming reaction and also produces the superoxide radical X O2-. While coenzyme-Q reacts with H+ ion, this superoxide radical X O2-, produce a state of scavenger wastage and hyperoxygenation of nicotinamide-adenine dinucleotide hydrogenase at two hours after injury. Lipid peroxigenation resulted from damage to the hydrogen electron transport system which created a state of energy metabolite disruption and cellular membrane damage and ultimately led to cellular autolysis.     

自血光量子疗法治疗实验性脊髓损伤

目的 探讨自血光量子疗法治疗脊髓损伤的作用机理。方法６０只家兔造成不全性脊髓损伤，分为损伤组和治疗组，进行脊髓血流量、脊髓诱发电位、丙二醇含量、钙组织化学染色和电镜的对比。结果自血光量子疗法能增加脊髓血流量；激活神经细胞的兴奋性和传导性；减轻自由基介导的脂质过氧化；阻滞钙经通道向细胞内流动；保护脊髓组织的超微结构。结论自血光量子疗法可以避免或减轻急性脊髓损伤后仍然存在的进行性，继发性损伤，促进脊髓功能恢复。     

Increased protein oxidation and decreased creatine kinase BB expression and activity after spinal cord contusion injury

Traumatic injury to the spinal cord triggers several secondary effects, including oxidative stress and compromised energy metabolism, which play a major role in biochemical and pathological changes in spinal cord tissue. Free radical generation and lipid peroxidation have been shown to be early events subsequent to spinal cord injury. In the present study, we demonstrated that protein oxidation increases in rat spinal cord tissue after experimental injury. As early as h after injury, the level of protein carbonyls at the injury epicenter was significantly higher than in control (169%, p < 0.05) and increased gradually over the next 4 weeks to 1260% of control level. Both caudal and rostral parts of the injured spinal cord demonstrated a mild increase of protein carbonyls by 4 weeks postinjury (135-138%, p < 0.05). Immunocytochemical analysis of protein carbonyls in the spinal cord cross-sections showed increased protein carbonyl immunoreactivity in the epicenter section compared to rostral and caudal sections of the same animal or control laminectomy animals. Increased protein carbonyl formation in damaged spinal cord tissue was associated with changes in activity and expression of an oxidative sensitive enzyme, creatine kinase BB, which plays an important role in the maintenance of ATP level in the CNS tissue. Damage to CK function in the CNS may severely aggravate the impairment of energy metabolism. The results of our study indicate that events associated with oxidative damage are triggered immediately after spinal cord trauma but continue to occur over the subsequent 4 weeks. These results suggest that antioxidant therapeutic strategies may be beneficial to lessen the consequences of the injury and potentially improve the restoration of neurological function.     

Spatial and temporal expression levels of specific microRNAs in a spinal cord injury mouse model and their relationship to the duration of compression

Background contextMicroRNAs, a class of small nonprotein-coding RNAs, are thought to control gene translation into proteins. The latter are the ultimate effectors of the biochemical cascade occurring in any physiological and pathological process. MicroRNAs have been shown to change their expression levels during injury of spinal cord in contusion rodent models. Compression is the most frequent mode of damage of neural elements in spinal cord injury. The cellular and molecular changes occurring in the spinal cord during prolonged compression are not very well elucidated. Understanding the underlying molecular events that occur during sustained compression is paramount in building new therapeutic strategies.PurposeThe purpose of our study was to probe the relationship between the expression level changes of different miRNAs and the timing of spinal cord decompression in a mouse model.Study designA compression spinal cord injury mouse model was used for the study.MethodsA laminectomy was performed in the thoracic spine of C57BL/6 mice. Then, the thecal sac was compressed to create the injury. Decompression was performed early for one group and it was delayed in the second group. The spinal cord at the epicenter of the injury and one level rostral to it were removed at 3, 6, and 24 hours after trauma, and RNA was extracted. Expression levels of six different microRNAs and the relationship to the duration of compression were analyzed. This work was supported in part by the University Research Council Grants Program at the University of Texas Health Science Center San Antonio (Grant 130267). There are no specific conflicts of interest to be disclosed for this work.ResultsExpression levels of microRNAs in the prolonged compression of spinal cord model were significantly different compared with the expression levels in the short duration of compression spinal cord injury model. Furthermore, microRNAs show a different expression pattern in different regions of the injured spinal cord.ConclusionsOur findings demonstrate that spinal cord compression causes alterations in the expression of different miRNAs in the acute phase of injury. Their expression is related to the duration of the compression of the spinal cord. These findings suggest that early decompression of the spinal cord may have an important modulating effect on the molecular cascade triggered during secondary injury through the changes in expression levels of specific microRNAs.     

Current and future surgery strategies for spinal cord injuries

Spinal cord trauma is a prominent cause of mortality and morbidity. In developed countries a spinal cord injury (SCI) occurs every 16 min. SCI occurs due to tissue destruction, primarily by mechanical and secondarily ischemic. Primary damage occurs at the time of the injury. It cannot be improved. Following the primary injury, secondary harm mechanisms gradually result in neuronal death. One of the prominent causes of secondary harm is energy deficit, emerging from ischemia, whose main cause in the early stage, is impaired perfusion. Due to the advanced techniques in spinal surgery, SCI is still challenging for surgeons. Spinal cord doesn’t have a self-repair property. The main damage occurs at the time of the injury primarily by mechanical factors that cannot be improved. Secondarily mechanisms take part in the following sections. Spinal compression and neurological deficit are two major factors used to decide on surgery. According to advanced imaging techniques the classifications systems for spinal injury has been changed in time. Aim of the surgery is to decompress the spinal channel and to restore the spinal alinement and mobilize the patient as soon as possible. Use of neuroprotective agents as well as methods to achieve cell regeneration in addition to surgery would contribute to the solution.     

Lipid peroxidation and the role of oxygen radicals in CNS injury

Lipid peroxidation is a radical induced chain reaction which is fundamentally linked to cellular destruction in the secondary injury process which is initiated by head and spinal injury and stroke. Injuries such as these begin a series of molecular events which lead to gradual vascular and neuronal degeneration. This process ultimately precludes neurological recovery. The secondary damage process is a combination of lipid peroxidation, calcium influx, arachidonic acid release and metabolism, transition metal redox reactions and tissue pH. Although CNS cells are particularly susceptible to lipid peroxidation, the process is common to many biological processes (e.g. inflammation, carcinogenesis, aging, radiation damage, transplant rejection, etc.).     

Gene therapy for spinal cord injury and disease

An incomplete understanding of the pathological processes involved in neurodegeneration and dysfunction of spinal cord injuries and diseases makes these disorders difficult to treat. Repair of damaged or genetically impaired spinal cord also has been limited by the complexity, cellular heterogeneity, and relative inaccessibility of the tissue. Thus, therapeutic options for the treatment of either chronic spinal cord diseases such as amyotrophic lateral sclerosis or acute spinal cord injuries have been rather limited. Potential new therapeutic targets are being identified as our understanding of the molecular pathology involved in neural injury and regeneration increases. Recent advances in gene transfer techniques have made gene therapy a more realistic and viable strategy for the treatment of a broad range of spinal cord disorders. This review summarizes the current state of knowledge regarding the limitations and recent advances in gene therapy and potential application of this technology toward spinal cord injury and disease.     

The role of directly applied hypothermia in spinal cord injury

STUDY DESIGN: The effect of intense local hypothermia was evaluated in a precision model of spinal canal narrowing and spinal cord injury in rats. The spinal cord injury was cooled with a custom cooling well used over the epidural surface. Basso, Beattie, and Bresnahan (BBB) motor scores and transcranial magnetic motor-evoked potential (tcMMEP) responses were used after injury to accurately evaluate neurologic recovery. OBJECTIVE: This study was undertaken to determine whether the prognosis for neurologic recovery in a standardized rat spinal cord injury model is altered by the direct application of precisely controlled hypothermia to the area of injury. SUMMARY OF BACKGROUND DATA: The role of hypothermia in the treatment of spinal cord injuries with neurologic deficits remains undefined. Hypothermia may decrease an area of spinal cord injury and limit secondary damage, therefore improving neurologic recovery. However, it has been difficult to consistently apply localized cooling to an area of spinal cord injury, and the use of systemic hypothermia is fraught with complications. This fact, along with the unavailability of a precise spinal cord injury model, has resulted in inconsistent results, both clinically and in the laboratory. In a rat model of spinal cord injury, 37 C and 19 C temperatures were used to study the role of hypothermia on neurologic recovery. METHODS: Male Spraque-Dawley rats (n = 52; weight, 277.7 g) were anesthetized with pentobarbital and subjected to laminectomy at T10. The rats were divided into three groups: 1) placement of a 50% spacer in the epidural space (16 rats), 2) severe (25 g/cm) spinal cord injury (16 rats), 3) 50% spacer in combination with spinal cord injury (16 rats). Eight rats in each group were tested at two temperatures: normothermic (37 C) and hypothermic (19 C). With the use of a specially designed hypothermic pool placed directly over the spinal cord for 2 hours, epidural heating to 37 C, and epidural cooling to 19 C was accomplished. Simultaneous measurements of spinal cord and body temperatures were performed. The rats underwent behavior testing using the BBB motor scores and serial tcMMEPs for 5 weeks. Statistical methods consisted of Student's t tests, one-way analysis of variance, Tukey post hoc t tests and chi2 tests. RESULTS: There was a significant improvement in motor scores in rats subjected to hypothermia compared with those that were normothermic after insertion of a 50% spacer. This improvement was observed during the 5-week duration of follow-up. In the severe spinal cord injury group and the spinal cord injury-spacer groups, no significant improvement in motor scores were obtained when the spinal cord was exposed to hypothermia. CONCLUSION: The results demonstrate that there is a statistically significant (P < 0.05) improvement in neurologic function in rats subjected to hypothermia (19 C) after insertion of a spacer that induced an ischemic spinal cord injury. This indicates that directly applied hypothermia may be beneficial in preventing injury secondary to ischemic cellular damage. The data demonstrated minimal therapeutic benefit of hypothermia (19 C) after a severe spinal cord injury.     

New pharmacological treatment of acute spinal cord trauma

Numerous experimental studies of blunt spinal cord injury have shown that while a variable degree of immediate mechanical damage occurs to spinal blood vessels and axons in proportion to the magnitude of the injury force, a considerable amount of post-traumatic tissue degeneration is due to a secondary pathophysiological process that may be modifiable by appropriate therapeutic intervention. A growing body of biochemical, physiological, and pharmacological evidence has suggested that oxygen free radical-induced lipid peroxidation, working in concert with aberrant calcium fluxes and eicosanoid generation in particular, plays a key role in progressive post-traumatic spinal cord degeneration. Of particular importance, lipid peroxidation has been linked to microvascular damage and hypoperfusion which, if severe enough, can lead to a secondary ischemic insult to the tissue. The ability of intensive dosing with the glucocorticoid steroid methylprednisolone to beneficially affect post-traumatic ischemia and to promote chronic neurologic recovery in spinal cord injured animals has been correlated not with its glucocorticoid activity, but rather with the ability to inhibit post-traumatic spinal lipid peroxidation. In view of this, a novel series of non-glucocorticoid 21-aminosteroids has been developed which lack glucocorticoid activity but are more effective inhibitors of nervous tissue lipid peroxidation than the glucocorticoid steroids. One of these, U74006F, has now been studied in some detail and appears to be a promising new agent for the acute treatment of spinal cord (and brain) trauma. The background and pre-clinical development of this compound to date is reviewed.     

The painful consequences of peripheral injury

Peripheral damage is immediately assessed by the central nervous system by way of a gate control system so that the sensory outcome depends not only on the fact of the injury and the injury signals but also on other convergent impulses from the periphery and on descending controls from brain to spinal cord. However peripheral injury, particularly when nerves are affected, sets off a chain of slow reactions which start in the area of damage but spread centrally. There are the local inflammatory reactions which change the sensitivity of nerves or of sprouts growing from cut nerves. There are changes which move over the entire length of the damaged axon changing the dorsal root ganglia and the terminals of afferents within the spinal cord. The arrival of injury produced impulses in the spinal cord triggers changes with a latency of many minutes which persist for hours even if no further impulses arrive. These increases of excitability and expansion of receptive fields which are triggered by C fibres may be the basis of the secondary hyperalgesias and reflex changes associated with injury.