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.

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)

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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.

The validity of the somatosensory evoked potential as an intraoperative spinal cord monitor was evaluated in an experimental model of scoliosis in the rat and a Harrington distraction model of injury. Under these conditions, it was found that any change in latency or amplitude of the major negative wave above a certain level was a significant predictor of an adverse neurologic outcome. Changes in latency of 4% or greater and changes in amplitude of 50% or greater were unequivocal indicators of spinal cord injury. Postmortem analyses of the spinal neurotransmitter serotonin revealed that apparent false-positive results of the SEP were, in fact, true-positive results.