Spermatogenesis in early and chronic phases of experimental spinal cord injury in the rodent model.

A rodent model was used to study the degree and dynamics of potential spermatogenic alterations during both acute and chronic phases after experimental spinal cord injury (SCI). Sexually mature Sprague-Dawley rats underwent controlled impact SCI by exposure of the thoracic spine, T-10 laminectomy, and intraoperative somatosensory-evoked potential latency and amplitude. A 50 gm-cm SCI was produced in 35 experimental subjects. Sham surgery was performed on 16 control subjects through exposure of the dura without weight drop. SCI was verified by obliteration of the somatosensory-evoked potential following injury and subsequent neurologic assessment (modified hindlimb Tarlov scale) 4 weeks after injury. Flow cytometry with acridine orange as the DNA probe was used to measure potential spermatogenic alterations in testicular cell development and integrity of epididymal sperm chromatin structure between 2 and 20 weeks following SCI. Flow cytometric analysis revealed that nine of the 35 SCI animals demonstrated altered spermatogenesis; it is not clear whether these effects are specific or nonspecific stress related. These responder animals contributed to dramatic differences in relative percent testicular haploid cells (spermatids) and concurrent differences in percent diploid cells at 2, 4, 8, 12, and 16 weeks. Percentages within the three spermatid populations (round, elongating, and elongated) also differed at these time points. The sperm chromatin structure assay (SCSA) revealed significant epididymal sperm nuclear structure differences at 2, 4, and 12 weeks (P < 0.001). These findings are in concordance with our clinical observations of spermatogenesis in spinal cord injured men and suggest that significant spermatogenic deficit may occur, even in the early phase of injury.

Anesthetic regimen effects on a pediatric porcine model of asphyxial arrest.

The effects of three anesthetic regimens on an established model of pediatric porcine hypoxic-hypercarbic arrest were examined. Twenty-four preadolescent miniature piglets were paralyzed, mechanically ventilated and anesthetized with one of three regimens: IM + IV pentobarbital (n = 8); IM + IV ketamine (n = 8); or IM ketamine+inhaled isoflurane (n = 8). Asphyxial cardiopulmonary arrest was induced and, after and 8 min cardiac arrest nonintervention interval, a standardized protocol of manual CPR with mechanical ventilation was performed. Outcome variables included incidence of ventricular fibrillation, time to cardiac arrest, endogenous plasma epinephrine levels and arteriovenous epinephrine gradients. IV Ketamine anesthesia produced the highest incidence of ventricular fibrillation (P < 0.01 vs. pentobarbital and isoflurane). Time to asphyxia induced cardiac arrest was greatest for the pentobarbital group (P < 0.05 vs. ketamine and isoflurane). During induction of asphyxial cardiac arrest (low cardiac flow), endogenous venous epinephrine accumulation was highest in the pentobarbital anesthetized group (P < 0.05). After 8 min of untreated cardiac arrest and 1 min of CPR (low flow), arterial epinephrine levels were highest in the ketamine group (P < 0.05). Endogenous epinephrine gradients were venous > arterial in all groups at the end of the 8 min cardiac arrest non-intervention interval (no flow). After 1 min of CPR, the gradients had either equalized or reversed to arterial > venous in all groups except for pentobarbital. As designed and expected, return of spontaneous circulation did not occur in any animal. We conclude that, in developing models of porcine asphyxial cardiopulmonary arrest and resuscitation to simulate pediatric human arrest, variations in anesthetic regimen produce significant differences in parameters that are important to consider: time to asphyxia induced cardiac arrest, fibrillation threshold, plasma epinephrine level and arteriovenous epinephrine gradient. Anesthetic effects need to be carefully considered and clearly explained to facilitate the interpretation of studies of interventions in cardiopulmonary arrest and resuscitation.

MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. Multicenter Animal Spinal Cord Injury Study.

The Multicenter Animal Spinal Cord Injury Study (MASCIS) adopted a modified 21-point open field locomotor scale developed by Basso, Beattie, and Bresnahan (BBB) at Ohio State University (OSU) to measure motor recovery in spinal-injured rats. BBB scores categorize combinations of rat hindlimb movements, trunk position and stability, stepping, coordination, paw placement, toe clearance, and tail position, representing sequential recovery stages that rats attain after spinal cord injury. A total of 22 observers from 8 participating centers assessed 18 hindlimbs of 9 rats at 2-6 weeks after graded spinal cord injury. The observers were segregated into 10 teams. The teams were grouped into 3 cohorts (A, B, and C), consisting of one experienced team from OSU and two non-OSU teams. The cohorts evaluated the rats in three concurrent and sequential sessions. After viewing a rat for 4 min, individual observers first assigned scores without discussion. Members of each team then discussed and assigned a team score. Experience (OSU vs. non-OSU) and teamwork (individual vs. team) had no significant effect on mean scores although the mean scores of one cohort differed significantly from the others (p = 0.0002, ANOVA). However, experience and teamwork significantly influenced reliability of scoring. OSU team scores had a mean standard deviation or discordance of 0.59 points, significantly less than 1.31 points for non-OSU team scores (p = 0.003, ANOVA) and 1.30 points for non-OSU individual scores (p = 0.001, ANOVA). Discordances were greater at the upper and lower ends of the scale, exceeding 2.0 in the lower (< 5) and upper (> 15) ends of the scale but were < 1.0 for scores between 4 and 16. Comparisons of non-OSU and OSU team scores indicated a high reliability coefficient of 0.892 and a correlation index (r2) of 0.894. These results indicate that inexperienced observers can learn quickly to assign consistent BBB scores that approach those given by experienced teams, that the scores are most consistent between 4 and 16, and that experience improves consistency of team scores.

Spinal endothelin content is elevated after moderate local trauma in the rat to levels associated with locomotor dysfunction after intrathecal injection.

The role of endothelin (ET) in the pathophysiology of secondary neural damage after experimental spinal cord injury (SCI) was examined in a rat model of weight-drop contusion injury. Initial studies demonstrated a significant increase in spinal ET concentrations in a 7.5-mm segment of tissue (centered at the impact site) at 30 min, 4 h, and 24 h after a moderate (50 g-cm) contusion injury. Subsequent experiments were aimed at reproducing these elevations by the intrathecal (i.t.) administration of ET and observing the effect on locomotor function. These studies showed that i.t. dosage of 9.6 ng produced spinal cord elevations of ET similar to those seen 30 min after moderate SCI as well as mild locomotor deficits. A 48 ng dose of ET resulted in moderate to severe locomotor deficits that were associated with spinal ET elevations much greater than those seen after injury. The mild deficits attributable to the lower dose of ET could contribute to the pathophysiological actions of other purported secondary injury mediators. The more pronounced locomotor deficits associated with the higher dose could be of relevance for severe SCI.

Interleukin-1 beta enhances spinal cord blood flow after intrathecal administration in the normal rat.

The effects of acute intrathecal recombinant human interleukin-1 beta (rhIL-1 beta) administration on spinal cord blood flow (SCBF), volume, and velocity were determined by laser-Doppler flowmetry in normal anesthetized rats with the use of a randomized and blinded protocol. The intrathecal administration of rhIL-1 beta (0.16-16 ng) produced a dose-dependent increase in SCBF that was not related to changes in blood pressure; arterial pH, PO2, PCO2; or spinal cord temperature. The IL-1 beta-induced enhancement of SCBF was directly proportional to the resultant elevation of spinal cord rhIL-1 beta content and was significantly correlated with an elevated blood velocity. The IL-1 receptor antagonist (IL-1ra) in concentrations 50- and 200-fold higher than IL-1 beta completely blocked the IL-1 beta-induced increase in SCBF when both compounds were administered concomitantly, but when administered alone, IL-1ra did not affect SCBF or other parameters. This suggests that IL-1 beta action was mediated by a specific interaction with an IL-1 membrane receptor site. The results suggest a role of IL-1 beta in the regulation of spinal cord hemodynamics. A potential pharmacological approach using IL-1 agonists for the treatment of the delayed appearance of posttraumatic spinal ischemia is proposed.

Erectile response to topical, intraurethral and intracorporal pharmacotherapy in a rat model of spinal cord injury.

In order to compare the erectile response to topical, intraurethral and intracorporal administration of vasoactive substances in neurologically intact and spinal cord injured (SCI) rats, a standard rat model of SCI using impact trauma at the level of T10 was employed, comparing the tumescence of 24 SCI and 25 control rats. Four weeks after SCI, the effect of vasoactive substances on erectile function was evaluated. Under ketamine anesthesia, the penis was exposed and intracorporal pressure (ICP) was monitored using saline infusion cavernosometry through a 24-gauge catheter inserted into one corpus cavernosum. Changes in ICP were recorded in response to the topical and intraurethral (IU) application of minoxidil (0.1 ml, 2% solution) and 2% nitroglycerin (NTG) ointment (0.1 gm), as well as the intracorporal (IC) administration of papaverine (0.0001-0.10 mg/kg). Results indicated that the mean baseline ICP was 8 +/- 5 mmHg for SCI and 9 +/- 4 mmHg for control rats. No response to topical therapy onto the undegloved penis was noted in either SCI or control rats. IU application of minoxidil to the degloved phallus developed ICP greater than that achieved with topical minoxidil; the topical application of NTG was less effective. In SCI rats, IC papaverine injection achieved an ICP of 56.9 +/- 24.3 mmHg, whereas papaverine in control rats generated an ICP of 43.5 +/- 38.8 mmHg. A greater increase in ICP at lower doses of each agent occurred in SCI than in control rats. We conclude that only the degloved phallus responded to topical vasoactive pharmacotherapy. Although both topical and IU applications of NTG and minoxidil increase ICP, tumescence was significantly less than that achieved with IC injection of papaverine. The IU application of minoxidil demonstrated significantly greater activity than other topical therapies. SCI rats displayed a supersensitive response to all modes of pharmacologic erectile therapy.

Autonomic dysreflexia in a rat model spinal cord injury and the effect of pharmacologic agents.

The object of this study was to develop a spinal cord injury (SCI) rat model for autonomic dysreflexia (AD), assessing the effect of alpha-adrenergic and calcium channel blockade and to determine the relationship of detrusor-external sphincter dyssynergia (DESD) to the development of AD. A laminectomy was performed in male rats at the T4 or T10 level and a controlled 50 g cm blunt SCI was induced using an impounder. Four weeks after injury, changes in arterial blood pressure and heart rate were monitored while simultaneous cystometry (CMG) and pelvic floor electromography (EMG) were performed in vivo in sham (control) and spinal cord injured rats. The effects of terazosin (0.1 mg/kg), diltiazem (0.5 mg/kg), and oxybutynin chloride (0.1 mg/kg) on hemodynamic changes were assessed independently. Both T4 and T10 SCI rat displayed evidence of DESD (enhanced pelvic floor EMG activity at cystometric capacity) while control rats did not. Only T4 injured rats exhibited evidence of AD, with mean blood pressure elevations from 82.9 +/- 13.6 to 93.9 +/- 11.3 mm Hg (P < 0.01) and a mean heart rate decrease from 332.2 +/- 56.5 to 311.1 +/- 54.5 beats/min (P = 0.02) at cystometric capacity. The intravenous administration of terazosin or diltiazem abolished the AD response during CMG. The administration of oxybutynin exhibited the ability to increase bladder capacity and improve compliance in all 3 groups but did not blunt AD. The rat model of SCI effectively reproduced hemodynamic changes consistent with the AD complex in T4 level SCI but not T10 level SCI animals, despite incomplete lesions. Blockade with either an alpha-1 or a calcium channel antagonist effectively ablated the AD response to bladder distention. Anticholinergic agents had no effect on AD. DESD frequently accompanies autonomic dysreflexia, although the development of AD is not a prerequisite for DESD.

Inspiratory-cycle instillation of endotracheal epinephrine in porcine arrest.

OBJECTIVE: To compare timed inspiratory-cycle endotracheal (ET) instillation of epinephrine (EPI) with instillation during apnea during CPR. METHODS: Prospective randomized laboratory comparison of two ET-EPI instillation techniques in 24 preadolescent anesthetized and paralyzed Yucatan swine (mean weight 10.3 +/- 1.5 kg) with apnea-induced hypoxic and hypercarbic cardiopulmonary arrest. After 8 minutes of cardiopulmonary arrest and 1 minute of CPR, 500 microgram(s) (50 +/- 7 microgram(s)/kg) of radiolabeled ET EPI was either administered timed to a ventilator inpspiratory cycle (IN, n = 15) or injected during apnea (DA, n = 9) using a monitoring lumen built into the sidewall of the ET tube. Injection technique was carefully controlled regarding ET-tube position, dilution, flush, and pressure-limited mechanical ventilations. CPR was resumed and continued for 5 minutes. If resuscitation occurred, monitoring was continued for one hour. Outcome variables included pulmonary EPI distribution pattern (DIST), plasma exogenous and total EPI levels, successful resuscitation, and hemodynamic response. RESULTS: Bilateral DIST occurred in 58% of the pigs, with significantly more bilateral DISTs for IN versus DA pigs (p = 0.01). Plasma radiolabeled exogenous EPI counts were significantly greater for IN versus DA pigs (p = 0.03). Total plasma EPI levels rose significantly above baseline over time within each group, but showed no difference between the IN and DA groups at any time point. Successful resuscitation occurred in 21% of the pigs, with no difference between IN and DA pigs (p = 0.38). CONCLUSION: When other aspects of ET EPI instillation are optimized and controlled during porcine hypoxic-hypercarbic arrest, timed inspiratory-cycle installation of ET EPI (50 microgram(s)/kg) results in an improved bilateral DIST and greater exogenous EPI absorption. However, in this severe pediatric asphyxial arrest model using a 50-microgram(s)/kg dose, inspiratory-cycle instillation does not improve the resuscitation rate or hemodynamic response over currently recommended instillation during apnea.

Effects of different techniques of endotracheal epinephrine administration in pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest.

OBJECTIVE: To compare three endotracheal epinephrine instillation techniques in a pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest model. DESIGN: Prospective, randomized, laboratory comparison of three instillation techniques. SETTING: Large animal research facility at a children's hospital. SUBJECTS: Thirty-six preadolescent anesthetized and paralyzed Yucatan swine (mean weight 10.0 +/- 1.9 kg) with apnea-induced hypoxic and hypercarbic cardiopulmonary arrest. INTERVENTIONS: After 8 mins of cardiopulmonary arrest and 1 min of cardiopulmonary resuscitation (CPR), 500 micrograms (51 +/- 9 micrograms/kg) of radiolabeled endotracheal epinephrine was administered by direct injection (n = 17), injection via feeding catheter (n = 10), or via monitoring lumen built into the sidewall of the endotracheal tube (n = 9). CPR was resumed and continued for 5 mins. If resuscitation occurred, monitoring was continued for 1 hr. Outcome variables included successful resuscitation, pulmonary distribution, heart rate, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations. Analysis by Fisher's exact test, one-way analysis of variance and Pearson's phi coefficient was performed. MEASUREMENTS AND MAIN RESULTS: Successful resuscitation occurred in 31% of all pigs with no difference between groups (p = .69). Bilateral distribution occurred in 39% with no difference between groups (p = .25). No correlation was noted between successful resuscitation and distribution (p = .65). HR, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations showed significant changes over time within groups, but no difference between groups at any time point. Adherence of the epinephrine dose to the endotracheal tube was < or = 1.5% in all cases. CONCLUSIONS: Instillation of 50 micrograms/kg of endotracheal epinephrine by three different techniques during pediatric porcine asphyxial arrest does not affect resuscitation rate, pulmonary distribution, hemodynamic response, or plasma exogenous and total epinephrine concentrations. No correlation was found between successful resuscitation and bilateral distribution. Therefore, currently recommended cumbersome endotracheal epinephrine instillation techniques may offer no resuscitation advantage over commonly used direct injection in this setting.

Characterization of mianserin neuroprotection in experimental spinal trauma: dose/route response and late treatment.

The neuroprotective action of the 5-hydroxytryptamine (5-HT2/5-HT1C) antagonist mianserin was examined with respect to optimal dosage, route of administration and time of treatment after a moderate spinal impact trauma (50 g.cm by the weight-drop method) to the thoracic region of the rat. In a previous study (Salzman et al., 1991b) a single 1-mg/kg i.v. dose of mianserin improved multiple measures of functional outcome when given 15 min after injury, whereas higher doses (5 and 10 mg/kg i.v.) displayed lesser therapeutic actions as well as pulmonary depressant effects. In these studies, lower dosages of minanserin (0.5 and 0.1 mg/kg i.v.) also were not associated with neuroprotection. Although the 1-mg/kg i.v. dosage again displayed significant efficacy when administered at 15 min delaying treatment to 30 min resulted in only marginal therapeutic actions. Nonetheless, i.p. dosage of 10 mg/kg (but not 2.5 mg/kg) at 15 min retained therapeutic efficacy, suggesting a pharmacodynamic influence. In support of this conclusion, the intrathecal administration of a 50-fold lower dose of minanserin (0.006 mg) at 15 min after injury resulted in neuroprotection that was superior to that of peripheral doses and was retained when this intrathecal dosage was administered at 1 hr after trauma. These results suggest a central mechanism of action for mianserin. Consistent with this was the lack of effect of mianserin (1 mg/kg i.v. at 15 min) upon post-traumatic spinal edema but its ability to reverse the decrease in central 5-HT oxidative metabolism after injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Detrusor-myoplasty, innervated rectus muscle transposition study, and functional effect on the spinal cord injury rat model.

The purpose of this investigation was to determine the feasibility of striated muscular augmentation of the urinary bladder (detrusor-myoplasty, DMP). Initial studies, transposition, and bladder wrap using several distinct muscle groups was attempted in laboratory rats, goats, and fresh human cadavers. The rectus abdominus muscle was found to be best suited to completely encompass the bladder with an intact neural and vascular supply. The technique was then applied in a rat model of spinal cord injury (SCI). Modified Tarlov ratings were employed to assess neurologic function 30 days after SCI. The median final neurological score of SCI rats with and without DMP was 4 and 5, respectively. Sham-operated SCI (control) rats, with and without DMP, both had normal final Tarlov scores of 12 (P < 0.05). Muscle blood flow values for the flap and the contralateral undissected rectus muscles were not significantly different (97 +/- 34 and 105 +/- 40 ml/100 g tissue/min, respectively, P = 0.47). Postoperatively, no bowel or abdominal wall functional deficits were apparent. The rotated muscular flap remained innervated and vascularized. Analysis of 24 hr micturition patterns demonstrated no differences in oral fluid intake/24hr, voided volume/24hr, and ratio of number of micturitions during the night vs. day among the four groups: (1) control (neither SCI nor DMP), (2) DMP only, (3) SCI only, and (4) SCI with DMP. Spinal cord injured rats with and without detrusor-myoplasty demonstrated a significant decrease in the number of micturitions/24hr, an increased volume per micturition, and greater largest and smallest micturition volumes (P < 0.05) when compared to controls. The micturition patterns among SCI rats with and without DMP were similar, as were non-SCI animals with and without DMP. This is the first report of the principle and technique of detrusor-myoplasty. Dissection of rats, goats, and human cadavers revealed that a vascularized and innervated rectus muscle flap can be rotated into the pelvis and wrapped around the bladder without tension. Significant loss of bladder capacity did not occur with skeletal muscle adaptation. Detrusor-myoplasty may be applicable for patients with an areflexic detrusor and non-intact sacral motor roots who are not candidates for sacral anterior root neurostimulation.

Micturition patterns after spinal trauma as a measure of autonomic functional recovery.

The purpose of these experiments was to determine whether experimental spinal trauma would result in urological dysfunction similar to that seen clinically and whether recovery of normal micturition can be correlated with motor functional recovery. A standard rat model of spinal impact trauma was employed. Neurologic evaluation included a modified 7 point hindlimb Tarlov scale applied weekly for 4 weeks after injury. Micturition measurement was accomplished by placing the animal in a metabolic cage for 24-hour periods and collecting urine on an electronic scale connected to Lotus Measure data acquisition software. All assessments were performed in a blinded fashion. Animals were categorized as normal control (N = 10), sham injured (N = 11), spinal cord injury (SCI) without (N = 11) and with locomotor recovery (N = 11). There were no differences in total micturition volume among the 4 groups, while the number of micturitions per 24 hours was significantly less for SCI without locomotor recovery (10.4 +/- 5.9) than for control (21.3 +/- 4.5). The volume per micturition was significantly greater for SCI (2.0 +/- 0.7 ml.) than for control (0.8 +/- 0.2 ml.). There were no differences among groups in the ratio of number of micturitions night/day. The SCI group had significantly greater largest and smallest micturitional volumes. Results clearly show alterations in micturition patterns induced by SCI. These were proportional to, but did not correlate fully with, the severity of injury and degree of motor recovery. Thus, recovery of a normal micturition pattern did not occur to the same extent as did motor functional recovery. This difference underscores the potential value of autonomic measures of SCI for distinguishing outcome categories after experimental SCI.

Halothane anesthesia is neuroprotective in experimental spinal cord injury: early hemodynamic mechanisms of action.

The neuroprotective potential of halothane anesthesia was explored in a weight-drop model of spinal trauma in the rat (N = 252). In initial experiments, animals were subjected to 25, 50 or 100 g cm impact injuries at T10 during pentobarbital or halothane anesthesia and their outcomes determined using somatosensory-evoked potentials, blinded neurologic evaluations for two weeks, and post-mortem analysis of spinal serotonin levels. Subsequently, halothane anesthesia was combined with either pentobarbital or nitrous oxide or given as a late treatment to pentobarbital anesthetized rats subjected to 50 g cm injuries. A series of acute studies were then performed in order to assess the hemodynamic and respiratory concomitants of halothane vs. pentobarbital, as well as the effect of mechanical ventilation and bicarbonate treatment upon halothane neuroprotection. Finally, the effect of a 50 g cm impact upon local white matter spinal cord blood flow was measured during halothane or pentobarbital anesthesia using laser-Doppler flowmetry. Results demonstrate an active neuroprotective action for halothane anesthesia that is not altered by the presence of other anesthetics and is most prominent at severe injury levels. The data suggest the importance of immediate injury responses in this action. Late halothane treatment was ineffective when given as early as 10 minutes postinjury while both the electrophysiological and hemodynamic effects of halothane vs. pentobarbital were apparent during this 10 minute period. Thus, halothane was associated with the prevention of spinal ischemia during the first 10 minutes after trauma in comparison to pentobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

Substituted thiosemicarbazides and corresponding cyclized 1,3,4-oxadiazoles and their anti-inflammatory activity.

Several 1-(4-biphenoxyacetyl)-4-substituted arylthiosemicarbazides and their corresponding cyclized 2-(4-biphenoxymethyl)-5-arylamino-1,3,4- oxadiazoles were synthesized and characterized by elemental analyses and IR, mass, and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carrageenin-induced edema in rat paw. The anti-inflammatory activity possessed by substituted thiosemicarbazides [100 mg/kg, intraperitoneal(ip)] ranged from 22 to 68%, whereas substituted 1,3,4-oxadiazoles (100 mg/kg, ip) provided protection of 10-76%. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip), used as standard reference drugs, decreased edema in rat paw by 44.6 and 52.9%, respectively. All compounds (1 mM) possessed antiproteolytic activity that was reflected by their ability to cause in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin. This inhibition ranged between 43 and 72% for substituted thiosemicarbazides and 30 and 83% for substituted 1,3,4-oxadiazoles.

The serotonin antagonist mianserin improves functional recovery following experimental spinal trauma.

The ability of the serotonin antagonist mianserin to improve neurological recovery after graded impact trauma to the thoracic region of the spinal cord was compared to that of cyproheptadine and ketanserin in pentobarbital-anesthetized rats. Spinal cord injury was produced at T-10 by the weight-drop method and confirmed by the disappearance of the somatosensory-evoked response during the subsequent 15 minutes. In all experiments, drug or vehicle treatments were randomly administered as a single intravenous bolus 15 minutes after injury. Functional outcome was blindly assessed for 2 weeks after injury using a modified Tarlov scale, and in some cases, the Rivlin-Tator angleboard test. The survival of descending raphe-spinal axons was determined by the measurement of serotonin in postmortem spinal tissues located above and below the site of injury. In separate acute experiments, the physiological and hemodynamic correlates of a 50 gm cm injury and either mianserin or vehicle injection were examined, as were the effects on serotonin content and metabolism in spinal tissues harvested 30 minutes after injury. All doses of mianserin were associated with some index of improved recovery following a 50 gm cm injury, with a 1-mg/kg dose being clearly superior. Both ketanserin (0.1 mg/kg) and cyproheptadine (2 mg/kg) displayed marginal therapeutic actions for 50 gm cm injuries. In acute studies, mianserin at 1 mg/kg was associated with the preservation of posttraumatic spinal cord blood flow at T-12 as well as a pronounced alteration in postmortem spinal serotonin content and metabolism, in contrast to vehicle control treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety versus efficacy of spinal cord stimulation for the generation of motor-evoked potentials in the rat.

The relative safety and efficacy of direct versus indirect methods of spinal cord stimulation for the production of descending motor-evoked responses was studied in pentobarbital-anesthetized rats (n = 39). Electrical stimuli were delivered for 1 h, either directly to the cord dorsum using silver ball electrodes or indirectly through jeweler's screws implanted in the intact laminae. Compound muscle action potentials (CMAPs) were recorded differentially in the quadriceps and evaluated for their morphology and reproducibility. The traumatic effects of stimulation were assessed using intraoperative somatosensory-evoked potentials, blinded neurological examinations for 2 weeks postoperatively, and histopathological and neurochemical analyses in postmortem spinal tissues. In separate experiments, the neural substrates of the muscle-evoked response to indirect cord stimulation were examined. Direct, epidural stimulation of the spinal cord at intensities sufficient to elicit reproducible CMAPs consistently resulted in mild behavioral deficits (13 of 18 animals) that were accompanied by postmortem changes in spinal histology and chemistry. Some of these behavioral deficits (5 of 13 animals) were resolved at 2 weeks. There was rarely an early sign of motor or sensory conduction derangement in these animals. In 2 animals with severe behavioral dysfunction, the somatosensory-evoked response was abolished immediately after spinal stimulation. However, CMAP responses were unaltered. Examination of the strength-duration relationship for the production of threshold responses to translaminar constant current stimulation, as well as experiments using selective transection of the dorsal columns, revealed the CMAP responses to be neurally mediated and conducted through the cord independent of the ascending sensory tracts that mediate the rat's somatosensory-evoked response. Data are discussed in terms of the potential experimental usefulness of CAMPs elicited by indirect dorsal spinal stimulation.

Comparison of a serotonin antagonist, opioid antagonist, and TRH analog for the acute treatment of experimental spinal trauma.

The therapeutic efficacies of a serotonin antagonist (mianserin), an opioid antagonist (nalmefene), and a TRH analog (YM-14673) were compared in a well-characterized model of experimental spinal trauma in the rat. Injury was produced by the weight-drop method at T10 and confirmed by the disappearance of the somatosensory evoked response during the subsequent 15 minutes. Drug or vehicle treatments were administered randomly as a single intravenous bolus 15 minutes after injury. Functional outcome was blindly assessed for 2 weeks postinjury using a modified Tarlov scale and the Rivlin-Tator angleboard test. The survival of descending raphe-spinal axons was determined by measurement of serotonin in postmortem spinal tissues located above and below the injury, and histopathologic studies were carried out at the site of injury. All agents displayed similar and significant efficacies with respect to Tarlov and Rivlin-Tator measures of motor recovery and preservation of raphe-spinal fibers below the lesion site. In contrast, none of the agents were effective for preserving the central gray matter or myelin staining in the white matter in slices of tissue from the site of injury. Results are discussed in terms of the early treatment of spinal cord injury and future clinical trials.

Serotonergic response to spinal distraction trauma in experimental scoliosis.

The effects of distraction injury to the spinal cord on serotonin (5HT) content and metabolism in a rat model of scoliosis were studied. Previous studies in this laboratory (Salzman et al., 1987a) have identified the 5HT response as a major component of the posttraumatic progression of spinal injury after impact trauma in the rabbit. The present study was designed to determine the universality of this response by examining a different model of injury in a different species. The results demonstrate that distraction trauma in the rat, like impact injury in the rabbit, is associated with a rapid and robust increase in the local spinal cord content and metabolism of 5HT and a long-term depletion of 5HT below the site of injury. The roles of the blood platelet and the raphe-spinal tract in the acute response and the disruption of axoplasmic transport during the chronic phase of injury are discussed.