In vivo microdialysis was used to sample extracellular concentrations of amino acids in the dorsal lumbar spinal cord of freely moving rats. Changes in the extracellular concentrations of amino acids were measured in response to infusion of veratridine (180 microM), a sodium channel activator, as well as during acute noxious stimulation by an injection of 5% formalin into the metatarsal region of the hindleg. Veratridine produced a tetrodotoxin (TTX)-sensitive increase in the extracellular concentration of Glu. Concentrations of Asp, taurine, Ala, Asn, and Gly were not significantly elevated following veratridine stimulation. Intradermal injection of formalin produced a TTX-sensitive increase in Asp concentration and a non-TTX-sensitive increase in Glu concentration. These data support the hypothesis that Glu and Asp are dorsal horn neurotransmitters involved in nociception.

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmitters (e.g., glycine and dopamine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brain's extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1-, 5-, and 13-fold and by 4-, 9-, and 31-fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700-fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4-fold, but remained elevated throughout the 80-min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann-Whitney test). That glutamate and aspartate concentrations in the hippocampus co-vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

We subjected 10 New Zealand White rabbits to 10 minutes of global cerebral ischemia under either normothennic (37°C) or moderately hypothermic (29°C) conditions. Hippocampal concentrations of glutamate, aspartate, and glycine were monitored using in vivo microdialysis. Outcome was assessed by both neurological and neuropathologic criteria. Hypothermia afforded nearly complete protection from ischemic injury. Ischemia-induced increases in the concentrations of glutamate, aspartate, and glycine in the nonnothermic group (3, 12, and 3 times baseline) were strikingly attenuated in the hypothermic group. In addition, the prolonged postischemic elevation of glycine levels seen in the normothennic group was absent in the hypothermic group. These results suggest that the neuroprotective properties of hypothermia may reside, in part, in their ability to prevent increases in the extracellular concentrations of amino acids that enhance the activity of the /V-methyl-D-aspartate receptor complex. (Stroke 1991;22:666-673) I t has been known for decades that hypothermia confers protection against the neuronal injury produced by episodes of transient cerebral ischemia. The mechanism by which this protection is achieved is not fully understood. Hypothermia is known to decrease the cerebral metabolic rate, and there is good evidence that at least some of the neuroprotective properties of hypothermia are due to the associated decrease in metabolic demand.1 Similar degrees of metabolic suppression produced by barbiturates or isoflurane, however, have shown inconsistent benefits in terms of neurological outcome and degree of neuronal injury. "4 Furthermore, recent studies have shown that while modest hypothermia (33°C) does not preserve high-energy phosphates (e.g., adenosine triphosphate, phosphocreatinine) or prevent the accumulation of metabolic wastes (e.g., lactate), 5 it does confer histopathologic protection from ischemia. 6 From the

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Using in vivo microdialysis in the dorsal spinal cord of the rat, we have previously observed increases in glutamate and aspartate during exposure to a noxious stimulus. The present investigation was designed to determine whether these increases may be mediated by substance P. Infusion of 1 mM of substance P in the dialysis fluid increased the concentrations of glutamate and aspartate, similar to the response seen during noxious stimulation. In addition, substance P also increased the concentrations of the inhibitory amino acids glycine and taurine. Calcitonin gene-related peptide, previously shown to enhance substance P-induced biting and scratching behavior, produced no effect on amino acid release by itself but potentiated the apparent release of taurine by substance P. To assess the importance of substance P-induced amino acid release in sensory processing, we examined the influence of taurine and of excitatory amino acid antagonists on the biting and scratching behavior produced by excitatory amino acids and substance P. Taurine selectively inhibited only substance P-induced biting and scratching while excitatory amino acid antagonists inhibited only excitatory amino acid-induced behavior. To further explore the ability of taurine to inhibit the substance P-induced behavior, 3 tests of nociception were then used. Pretreatment with taurine inhibited the nociceptive-related writhing behavior produced by an intraperitoneal injection of acetic acid in mice but failed to alter the latency of response in the hot plate or tail flick assay.(ABSTRACT TRUNCATED AT 250 WORDS)