Biomedical subjects

C E Hulsebosch

Publications and source records attributed to C E Hulsebosch.

At least 19 recordsLinked to original sources

PubMed2003

Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat.

Hemisection of the rat spinal cord at thoracic level 13 provides a model of spinal cord injury that is characterized by chronic pain attributable to hyperexcitability of dorsal horn neurons. Presuming that this hyperexcitability can be explained in part by interruption of descending inhibitory modulation by serotonin, we hypothesized that intrathecal transplantation of RN46A-B14 serotonergic precursor cells, which secrete serotonin and brain-derived neurotrophic factor, would reduce this hyperexcitability by normalizing the responses of low-threshold mechanoreceptive, nociceptive-specific, and multireceptive dorsal horn neurons. Three groups (n=45 total) of 30-day-old male Sprague-Dawley rats underwent thoracic level 13 spinal hemisection, after which four weeks were allowed for development of allodynia and hyperalgesia. The three groups of animals received transplants of no cells, 10(6) RN46A-V1 (vector-only) or 10(6) RN46A-B14 cells at lumbar segments 2-3. Electrophysiological experiments were done two weeks later. Low-threshold mechanoreceptive, nociceptive-specific, and multireceptive cells (n=394 total) were isolated at depths of 1-300 and 301-1000 micro in the lumbar enlargement. Responses to innocuous and noxious peripheral stimuli were characterized, and analyses of population responses were performed. Compared with normal animals, dorsal horn neurons of all types in hemisected animals showed increased responsiveness to peripheral stimuli. This was true for neurons on both sides of the spinal cord. After hemisection, the proportion of neurons classified as multireceptive cells increased, and interspike intervals of spontaneous discharges became less uniform after hemisection. Transplantation of RN46A-B14 cells restored evoked responses to near-control levels, normalized background activity, and returned the proportion of multireceptive cells to the control level. Restoration of normal activity was reversed with methysergide.These electrophysiological results corroborate anatomical and behavioral studies showing the effectiveness of serotonergic neural precursors in correcting phenomena associated with chronic central pain following spinal cord injury, and provide mechanistic insights regarding mode of action.

Action Potentials↗

PubMed2002

DNA microarray analysis of the contused spinal cord: effect of NMDA receptor inhibition.

Spinal cord injury (SCI)-induced neurodegeneration leads to irreversible and devastating motor and sensory dysfunction. Post-traumatic outcomes are determined by events occurring during the first 24 hours after SCI. An increase in extracellular glutamate concentration to neurotoxic levels is one of the earliest events after SCI. We used Affymetrix DNA oligonucleotide microarrays (with 1,322 DNA probes) analysis to measure gene expression in order to test the hypothesis that SCI-induced N-methyl-D-aspartate (NMDA) receptor activation triggers significant postinjury transcriptional changes. Here we report that SCI, 1 hour after trauma, induced change in mRNA levels of 165 genes and expression sequence tags (ESTs). SCI affected mRNA levels of those genes that regulate predominantly transcription factors, inflammation, cell survival, and membrane excitability. We also report that NMDA receptor inhibition (with -(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate [MK-801]) reversed the effect of SCI on about 50% of the SCI-affected mRNAs. Especially interesting is the finding that NMDA receptor activation participates in the up-regulation of inflammatory factors. Therefore, SCI-induced NMDA receptor activation is one of the dominant, early signals after trauma that leads to changes in mRNA levels of a number of genes relevant to recovery processes. The majority of MK-801 effects on the SCI-induced mRNA changes reported here are novel. Additionally, we found that the MK-801 treatment also changed the mRNA levels of 168 genes and ESTs that had not been affected by SCI alone, and that some of their gene products could have harmful effects on SCI outcome.

Animals↗

PubMed2001

Subdural engraftment of serotonergic neurons following spinal hemisection restores spinal serotonin, downregulates serotonin transporter, and increases BDNF tissue content in rat.

Spinal hemisection injury at T13 results in development of permanent mechanical allodynia and thermal hyperalgesia due to interruption and subsequent loss of descending inhibitory modulators such as serotonin (5-HT) and its transporter (5-HT(T)). We hypothesize that lumbar transplantation of non-mitotic cells that tonically secrete 5-HT and brain-derived neurotrophic factor (BDNF) will restore alterations in 5-HT and 5-HT(T) systems within the spinal dorsal horn. We used an immortalized rat neuronal cell line derived from E13 raphe (RN46A-B14) which is shown to secrete 5-HT and BDNF in vitro and in vivo. Three groups (n=35) of 30 day old male Sprague-Dawley rats were spinally hemisected at T13 and 28 days later received either lumbar RN46A-V1 control empty-vector (n=15) or RN46A-B14 (n=15) intrathecal grafts, or no transplant. Twenty-eight days following transplantation, animals were perfused and tissue examined for changes in 5-HT, 5-HT(T), and BDNF at the site of transplantation or at lumbar enlargements (L5). Immunohistochemistry revealed that RN46A-B14, but not RN46A-V1 cells, increased 5-HT tissue staining at L5 in the dorsal white matter as well as in superficial dorsal horn laminae I and II on both ipsilateral and contralateral sides, results confirmed by ELISA. Transplantation of RN46A-B14 cells significantly reduced ipsilateral 5-HT(T), upregulated after injury. Significantly increased levels of BDNF were also observed after RN46A-B14 transplantation but were not localized to particular spinal laminae. These results are consistent with recovery of locomotor function and reductions in chronic pain behaviors observed behaviorally after RN46A-B14 transplantation and supports the pragmatic application of cell-based therapies in correcting damaged circuitry after spinal cord injury.

Animals↗

PubMed2001

Changes in metabotropic glutamate receptor expression following spinal cord injury.

Spinal cord injury (SCI) initiates biochemical events that lead to an increase in extracellular excitatory amino acid concentrations, resulting in glutamate receptor-mediated excitotoxic events. These receptors include the three groups of metabotropic glutamate receptors (mGluRs). Group I mGluR activation can initiate a number of intracellular pathways that increase neuronal excitability. Group II and III mGluRs may function as autoreceptors to modulate neurotransmission. Thus, all three groups may contribute to the mechanisms of central sensitization and chronic central pain. To begin evaluating mGluRs in SCI, we quantified the changes in mGluR expression after SCI in control (naive), sham, and impact injured adult male Sprague-Dawley rats (200-250 g). SCI was produced at spinal segment T10 with a New York University impactor (12.5-mm drop, 10-g rod of 2-mm diameter). Expression levels were determined by Western blot and immunohistochemistry analyses at the epicenter of injury, as well as segments rostral and caudal. The group I subtype mGluR1 was increased over control levels in segments rostral and caudal by postsurgical day (PSD) 7 and remained elevated through PSD 60. The group I subtype mGluR5 was unchanged in all segments rostral and caudal to the injury at every time point measured. Group II mGluRs were decreased compared to control levels from PSD 7 through PSD 60 in all segments. These results suggest that different subtypes of mGluRs have different spatial and temporal expression patterns following SCI. The expression changes in mGluRs parallel the development of mechanical allodynia and thermal hyperalgesia following SCI; therefore, understanding the expression of mGluRs after SCI may give insight into mechanisms underlying the development of chronic central pain.

Animals↗

PubMed2001

Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat.

Spinal cord injury (SCI) results in abnormal locomotor and pain syndromes in humans. T13 spinal hemisection in the rat results in development of permanent mechanical allodynia and thermal hyperalgesia partially due to interruption of descending inhibitory modulators such as serotonin (5-HT). We hypothesize that lumbar transplantation of nonmitotic cells that tonically secrete antinociceptive and trophic compounds will reduce the pain-like behavior and enhance locomotor recovery after SCI. We used RN46A-B14 cells, a conditionally immortalized (SV40tsTag) rat neuronal cell line derived from E13 raphe bioengineered to secrete both 5-HT and BDNF in vitro at both permissive (33 degrees C) and nonpermissive (39 degrees C) temperatures. Three groups (n = 72) of 30-day-old male Sprague-Dawley rats were spinally hemisected at T13 and allowed 4 weeks for adequate recovery of locomotor function and development of allodynia and hyperalgesia. Immunosuppressed animals received either lumbar RN46A-B14 (n = 24) or control RN46A-V1 (n = 24) empty-vector transplants or no cell (n = 24) transplant. HPLC analysis of media and CSF demonstrated increases of both in vitro and in vivo 5-HT levels at 28 days in RN46A-B14 animals. ELISA demonstrated BDNF secretion in vitro and in vivo by RNA46A-B14 cells. Locomotor function (BBB scale) and nociceptive behaviors measured by paw withdrawals to von Frey filaments, radiant heat, and noxious pin stimuli were tested for 4 weeks posttransplant. Animals receiving RN46A-B14 cells demonstrated significantly improved locomotor function and reductions in both fore- and hindlimb mechanical allodynia and thermal hyperalgesia compared to controls receiving RN46A-V1 or no transplants. These effects were modulated by the 5-HT antagonist methysergide and reuptake inhibitor fluvoxamine. Bromodeoxyuridine and 5-HT immunoreactivity confirmed cell survival and graft location 4 weeks posttransplantation. These results support the therapeutic potential of bioengineered serotonin-secreting cell lines in reducing chronic central pain following spinal cord injury.

Animals↗

PubMed2001

Involvement of metabotropic glutamate receptors in excitatory amino acid and GABA release following spinal cord injury in rat.

Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations resulting in glutamate receptor-mediated excitotoxic events. The glutamate receptors include ionotropic (iGluRs) and metabotropic (mGluR) receptors. Of the three groups of mGluRs, group-I activation can initiate intracellular pathways that lead to further transmitter release. Groups II and III mGluRs function mainly as autoreceptors to regulate neurotransmitter release. In an effort to examine the role of mGluRs in the increase in EAAs following SCI, we administered AIDA, a potent group-I mGluR antagonist immediately after injury. To determine subtype specific roles of the group-I mGluRs, we evaluated EAA release following LY 367385 (mGluR1 antagonist) and MPEP (mGluR5 antagonist) administration. To evaluate group-II and -III mGluRs we administered APDC (group-II agonist) and L-AP4 (group-III agonist) immediately following injury; additionally, we initiated treatment with CPPG (group-II/-III antagonist) and LY 341495 (group-II antagonist) 5 min prior to injury. Subjects were adult male Sprague-Dawley rats (225-250 g), impact injured at T10 with an NYU impactor (12.5 mm drop). Agents were injected into the epicenter of injury, amino acids where collected by microdialysis fibers inserted 0.5 mm caudal from the edge of the impact region and quantified by HPLC. Treatment with AIDA significantly decreased extracellular EAA and GABA concentrations. MPEP reduced EAA concentrations without affecting GABA. Combining LY 367385 and MPEP resulted in a decrease in EAA and GABA concentrations greater than either agent alone. L-AP4 decreased EAA levels, while treatment with LY 341495 increased EAA levels. These results suggest that mGluRs play an important role in EAA toxicity following SCI.

Animals↗

PubMed2001

Strain and model differences in behavioral outcomes after spinal cord injury in rat.

Spinal cord injury (SCI) results in loss of function below the level of injury and the development of chronic central pain (CCP) syndromes. Since different strains may develop and express chronic pain behaviors differently, we evaluated behavioral outcomes (locomotor recovery and the development of mechanical and thermal allodynia) in three commonly used strains of rats (Long-Evans, Wistar, and Sprague-Dawley) using two models of SCI. The two models examined were contusion at T10 (NYU impactor, 12.5 mm height) and the T13 hemisection. Mechanical stimulation (von Frey filaments) revealed significantly lower baseline responses for Long-Evans rats and significantly higher baseline paw withdrawal latencies to thermal stimulation for Wistar rats compared to the other strains. Following contusion SCI, Long-Evans rats had the highest percentage of animals that developed mechanical allodynia (73%), while Sprague-Dawley rats had the highest percentages (75%) following hemisection SCI. Interestingly, the Sprague-Dawley rats had the highest percentage (87%) to develop thermal allodynia following contusion SCI, while 100% of both Long-Evans and Sprague Dawley rats developed thermal allodynia in the hemisection model. Locomotor recovery after SCI was similar for each model in that Long-Evans rats recovered slower and to a lesser extent than the other strains. In each model, Sprague-Dawley rats recovered faster and achieved greater function. Overall, the hemisection model produced a larger percentage of animals that developed CCP and had greater responses to mechanical stimulation. Thus, it appears that strain selection has a greater impact on locomotor recovery and model selection has a greater impact on the development of CCP following SCI. Furthermore, these results suggest that genetic factors may play a role in recovery following SCI.

Animals↗

PubMed2001

Bcl-xL expression after contusion to the rat spinal cord.

After contusion-derived spinal cord injury, (SCI) there is localized tissue disruption and energy failure that results in early necrosis and delayed apoptosis, events that contribute to chronic central pain in a majority of patients. We assessed the extent of contusion-induced apoptosis of neurons in a known central pain-signaling pathway, the spinothalamic tract (STT), which may be a contributor to SCI-induced pain. We observed the loss of STT cells and localized increase of DNA fragmentation and cytoplasmic histone-DNA complexes, which suggested potential apoptotic changes among STT neurons after SCI. We also showed SCI-associated changes in the expression of the antiapoptotic protein Bcl-xL, especially among STT cells, consistent with the hypothesis that Bcl-xL regulates the extent of apoptosis after SCI. Apoptosis in the injured spinal cord correlated well with prompt decreases in Bcl-xL protein levels and Bcl-xL/Bax protein ratios at the contusion site. We interpret these results as evidence that regulation of Bcl-xL may play a role in neural sparing after spinal injury and pain-signaling function.

Animals↗

PubMed2001

Changes in exploratory behavior as a measure of chronic central pain following spinal cord injury.

Spinal cord injury (SCI) produces abnormal pain syndromes in patients that lead to changes in evoked and spontaneous behaviors. To test if a spontaneous component of pain-like behavior could be measured in a rodent model of chronic central pain (CCP), exploratory behavior (rearing events, rearing time, active time, rest time, distance traveled, and total activity) of adult male rats, subjected to sham surgery or spinal cord contusion injury treated with either vehicle (saline) or gabapentin (30 mg/kg, i.p.), was recorded. SCI was produced at spinal segment T10 using the NYU impactor device (10-g rod, 2.0-mm diameter, 12.5-mm drop height). Activity measures were collected on postsurgical days (PSD) 14, 28, and 60, and compared to presurgical activity. Sham control activity was not significantly different compared to presurgical activity in any measured parameter. SCI vehicle-treated rats demonstrated a significant decrease in total rearing time on PSD 14 and by PSD 28 significant differences in total activities where seen in all parameters measured. SCI gabapentin-treated rats did not display differences in total rearing time until PSD 28 and a significant difference in total activity of all measured parameters was not seen until PSD 60. No difference in hindlimb locomotor ability between SCI groups or sedation effects of gabapentin was found using open field BBB scores. We interpret the differences in exploratory behavior to reflect spontaneous behavioral changes due to CCP since (1) when locomotor ability was greatest, activity was lowest and (2) gabapentin attenuates the temporal decrease in activity. This study demonstrates that spontaneous as well as evoked behaviors may be used to evaluate CCP following SCI.

Acetates↗

PubMed2001

Reduction of pathological and behavioral deficits following spinal cord contusion injury with the selective cyclooxygenase-2 inhibitor NS-398.

Spinal cord injury (SCI) results in loss of locomotor function and development of abnormal chronic pain syndromes (mechanical allodynia, thermal hyperalgesia). Following injury, secondary mechanisms including release of excitatory amino acids, inflammation and lipid peroxidation damage neural cells through release of cytotoxic free radicals. We hypothesized that selective inhibition of cyclooxygenase-2 (COX-2), an inducible inflammatory mediator, would decrease tissue damage and subsequently reduce locomotor deficits and development of chronic central pain syndromes after injury. Fifteen minutes prior to receiving T13 spinal segment spinal cord contusion injury, 200-225-g male Sprague-Dawley rats received either vehicle (0.5 ml 1:1 v/v DMSO/saline, i.p., n = 20) or the selective COX-2 inhibitor NS-398 (5 mg/kg in DMSO/saline v/v, i.p., n = 20). Locomotor function via the BBB scale, and nociceptive behaviors measured by paw withdrawals to von Frey filaments and radiant heat stimuli were tested for 4 weeks postinjury. Histological examination and volumetric analysis of spinal cord tissue were performed concomitantly. Spinally contused animals receiving NS-398 demonstrated significantly (p < 0.05) reduced locomotor alteration and reductions in both fore- and hindlimb mechanical allodynia and thermal hyperalgesia when compared to vehicle controls. Histological examination of spinal segments at the lesion segment demonstrated reduced lesion extent and increased viable tissue when compared to vehicle controls. Prostaglandin E2 levels were significantly lowered in NS-398-treated but not vehicle-treated animals 12 h after injury. These results support the role of COX-2 in reducing pathological and behavioral deficits after spinal cord injury.

Animals↗

PubMed2000

AIDA reduces glutamate release and attenuates mechanical allodynia after spinal cord injury.

Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations, resulting in glutamate receptor-mediated excitotoxicity and central sensitization. To test contributions of group I metabotropic glutamate receptors (mGluRs) in SCI induced release of glutamate and in behavioral outcomes of central sensitization following injury, we administered 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.1 nmol intraspinally), a potent group I mGluR antagonist, to rats immediately after spinal cord contusion injury. EAAs were collected by microdialysis and quantified using HPLC. AIDA significantly decreased extracellular glutamate but not aspartate concentrations and significantly attenuated the development of mechanical but not thermal allodynia. These results suggest mGluRs play an important role in injury-induced EAA release and in central sensitization following SCI.

Animals↗

PubMed2000

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury.

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.

Animals↗

PubMed2000

Transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb allodynia in a rodent model of chronic central pain after spinal cord hemisection injury.

In the majority of patients, spinal cord injury (SCI) results in abnormal pain syndromes in which non-noxious stimuli become noxious (allodynia). To reduce allodynia, it would be desirable to implant a permanent biological pump such as adrenal medullary chromaffin cells (AM), which secrete catecholamines and opioid peptides, both antinociceptive substances, near the spinal cord. We tested this approach using a recently developed a mammalian SCI model of chronic central pain, which results in development of mechanical and thermal allodynia. Thirty day-old male Sprague-Dawley rats were spinally hemisected at T13 and allowed 4 weeks for recovery of locomotor function and development of allodynia. Nonimmunosuppressed injured animals received either control-striated muscle (n = 7) or AM (n = 10) transplants. Nociceptive behavior was tested for 4 weeks posttransplant as measured by paw withdrawals to von Frey filaments, radiant heat, and pin prick stimuli. Hemisected animals receiving AM demonstrated statistically significant reductions in both fore- and hindlimb mechanical and thermal allodynia, but not analgesia, when compared to hemisected animals receiving striated muscle transplants (P < 0.05). Tyrosine hydroxylase immunoreactivity indicated prolonged transplant survival and production of catecholamines. HPLC analysis of cerebrospinal fluid samples from animals receiving AM transplants demonstrated statistically significant increases in levels of dopamine (sevenfold), norepinephrine (twofold), and epinephrine (threefold), compared to control values several weeks following transplant (P < 0.05). By 28 days posttransplant, however, antinociceptive effects were diminished. These results support the therapeutic potential of transplanted AM in reducing chronic central pain following spinal cord injury.

Adrenal Medulla↗

PubMed2000

Alleviation of mechanical and thermal allodynia by CGRP(8-37) in a rodent model of chronic central pain.

CGRP(8-37) is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP(8-37) on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague-Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and thermal allodynia bilaterally, in both forelimbs and hindlimbs. CGRP(8-37) was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 microl volumes. CGRP(8-37) was effective in alleviating mechanical and thermal allodynia in a dose-dependent manner (P<0.05). The 50 nM dose was most efficacious for both forelimb and hindlimb responses (P<0.05). The period of efficacy was 10 min to onset for a duration of 20 min. Post-drug washout responses were not statistically significant compared to pre-drug responses. The sham control groups demonstrated no statistically significant difference at any dose of CGRP(8-37) when compared to pre-surgical baseline values. In conclusion, CGRP(8-37) is effective in abolishing mechanical and thermal allodynia produced by spinal hemisection. Consequently, the CGRP receptor may play a role in chronic central neuropathic pain and offers a novel therapeutic approach to managing chronic central pain.

Animals↗

PubMed2000

Bridging the gap: from discovery to clinical trials in spinal cord injury.

Recently, the Kent Waldrep National Paralysis Foundation initiated a think tank intended to bridge several gaps and achieve several goals in regard to spinal cord injury (SCI) research and funding. Affiliated with the need to bridge a pathophysiological gap in spinal parenchyma and/or reorganize remaining circuitry after injury is a need to bridge resource gaps for timely funding for translational research, gaps in knowledge between researchers, and between researchers/clinicians and SCI patients. The epistemology of cure was examined and redefined to include transitional recoveries and advances. Modes and mechanisms of funding have been evaluated and where deficits were perceived, suggestions have been made to expedite and increase the number and breadth of funding opportunities. Innovative infrastructure changes are submitted. We discuss the progression of clinical trials as well as offer suggestions to facilitate benchtop-to-bedsite translation of valuable research to the customer. Highlights of recently completed, in progress, and future trials are detailed. Finally, we submit five essential processes required to promote advances to the SCI patient population: discovery, development, clinical trials, evaluation, and rehabilitation. These ideas are intended to facilitate entry of serious dialogue and to ultimately improve the lives of patients living with SCI.

Clinical Trials as Topic↗

PubMed2000

Rodent model of chronic central pain after spinal cord contusion injury and effects of gabapentin.

Spinal cord injury (SCI) often results in abnormal pain syndromes in patients. We present a recently developed SCI mammalian model of chronic central pain in which the spinal cord is contused at T8 using the NYU impactor device (10-g rod, 2.0-mm diameter, 12.5-mm drop height), an injury which is characterized behaviorally as moderate. Recovery of locomotor function was assessed with an open field test and scored using the open field test scale (BBB scale). Somatosensory tests of paw withdrawal responses accompanied by supraspinal responses to both mechanical punctate (von Frey hairs) and nonpunctate (4 mm diameter blunt probe) as well as thermal (radiant heat) peripheral stimuli were performed. Comparisons at the level of the individual animal between precontusion and postcontusion responses indicated significant increases in reactions to low threshold punctate mechanical stimuli, non-punctate stimuli and thermal stimuli (p < 0.05). To demonstrate the validity of this model as a central pain model, gabapentin, an agent used clinically for central pain, was given i.p. at 10 or 30 mg/kg. Gabapentin treatment significantly and reversibly changed the responses, consistent with the attenuation of the abnormal sensory behavior, and the attenuated responses lasted for the duration of the drug effect (up to 6 h). These results support the use of the spinal contusion model in the study of chronic central pain after SCI.

Acetates↗

PubMed1999

NGF levels decrease in the spinal cord and dorsal root ganglion after spinal hemisection.

To examine changes in nerve growth factor (NGF) levels in spinal cord and dorsal root ganglia (DRG) after spinal injury, male Sprague-Dawley rats weighing 150-175 g were given spinal hemisections. NGF content was measured at various post-surgical times and compared with naive controls (n = 4 per time point) in the spinal cord, DRG and blood serum by ELISA techniques (Promega). Levels of NGF in the blood serum were significantly increased 8-fold at 48h but were significantly decreased in the spinal cord and DRG by 2- to 4-fold until 7 days postsurgery (ANOVA, p < 0.05). Contrary to accepted dogma, spinal injury results in decreased levels of NGF in the spinal cord and DRG following spinal injury.

Animals↗

PubMed1998

Traumatic brain injury in rats results in increased expression of Gap-43 that correlates with behavioral recovery.

Traumatic brain injury is associated with behavioral deficits, often in the absence of histopathological or ultrastructural changes. To determine whether membrane remodeling occurs, immunocytochemical techniques were used and the density and distribution of GAP-43 were measured. GAP-43 is a membrane-bound protein, which, when phosphorylated, is thought to regulate metabolic pathways involved in membrane remodeling and neurite growth. Moderate central fluid percussion injury (FPI, 1.9-2.2 atm.) was performed on anesthetized, spontaneously hypertensive Wistar rats (SHR). Behavioral reflex recovery was consistent with moderate levels of brain injury. One, 3, 5, 7 and 9 days after injury, both sham control (n = 4) and FPI (n = 4) animals were sacrificed, the brains were removed, cryosectioned and processed. Density measurements were taken from histological sections taken at interaural 6.20 mm and bregma -2.80 mm and were found to be statistically greater (P < 0.05) than background grey matter readings in the agranular cortices, the frontal, hindlimb, parietal 1 and 2 cortices, and the hippocampus and dentate gyrus, excluding the pyramidal and granular cell layers. Density measurements taken in forelimb and hindlimb cortical regions correlate with forelimb and hindlimb recovery in foot-fault and beam balance tests (P < 0.05). We interpret these data to indicate neuronal membrane remodeling as a result of the disruption of neuronal membranes due to the impact and shearing forces associated with the FPI. The disruption and remodeling of neuronal membranes are in areas that are consistent with the loss and recovery of locomotor and spatial behavior as a result of FPI.

Animals↗