Recovery of brain dopamine metabolism by branched-chain amino acids in rats with acute hepatic failure.

A decrease in the serum ratio of branched-chain amino acids (BCAAs) to aromatic amino acids (Fischer ratio) reflects the severity of hepatic encephalopathy, and clinical improvement by dietary augmentation with BCAAs has been demonstrated. As behavioral alteration results from changes in central neurotransmission, we investigated the role of BCAA administration on changes in the levels of central neurotransmitters in acute liver injury. Male Wistar rats were subjected to liver ischemia by occluding the left portal vein and hepatic artery for 90 minutes. A 4% BCAA solution containing valine, leucine, and isoleucine was intraperitoneally administered 3 times (8 mL/kg, each) at 1 hour, 6 hours, and 24 hours after vascular reperfusion, and changes in the extracellular concentrations of neurotransmitter amino acids, monoamines, and their metabolites were evaluated in the striatum by a microdialysis procedure. Although the extracellular concentration of dopamine was affected by neither liver ischemia nor BCAA injections, the level of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 34% in the ischemic group 24 hours after reperfusion. The 3,4-dihydroxyphenylacetic acid level was normalized by treatments with BCAAs. The improvement of deranged cerebral dopaminergic activity may be a contributing factor in the improvement of hepatic encephalopathy by BCAAs.

The differential effects of halothane and isoflurane on windup of dorsal horn neurons selected in unanesthetized decerebrated rats.

Halothane and isoflurane, in the peri-minimum alveolar anesthetic concentration (MAC) range, exert differential effects on spinal nociceptive neurons, whereby halothane further depresses their responses from 0.8 to 1.2 MAC, whereas isoflurane does not. We presently investigated if these anesthetics differentially affect windup, the progressive increase in neuronal responses to repetitive noxious stimuli, over a broad concentration range from 0 to 1.2 MAC. In decerebrated rats, single-unit recordings were made from dorsal horn neurons exhibiting windup to 20 1-Hz C-fiber strength electrical stimuli. Halothane and isoflurane (0, 0.4, 0.8, and 1.2 MAC) were tested in a counterbalanced crossover protocol. Increasing halothane and isoflurane from 0 to 1.2 MAC progressively suppressed the response to the first stimulus, as well as summed responses to all stimuli (to 34% +/- 8% and 50% +/- 8%, respectively; P < 0.05). Absolute windup (summed response minus 20x the first response) was suppressed by both anesthetics from 0 to 0.8 MAC, with further depression by halothane but not isoflurane at 1.2 MAC. Responses of neurons isolated at 0 MAC were partially, but never totally, depressed at 0.8 MAC. The dose-dependent suppression of windup is consistent with reduced temporal summation of pain. Further depression at 1.2 MAC halothane, but not isoflurane, suggests different sites of immobilizing action for these two anesthetics. Immobility seems to not be mediated by severe anesthetic depression of a subpopulation of nociceptive neurons.

Etomidate depresses lumbar dorsal horn neuronal responses to noxious thermal stimulation in rats.

Etomidate is a widely used IV anesthetic, but little is known about its analgesic properties, in particular, its effects on spinal cord neuronal responses to noxious stimuli. We hypothesized that etomidate would depress lumbar neuronal responses to noxious heat. Rats (n = 15) were anesthetized with isoflurane (1.2%) and laminectomy was performed to record single unit activity. Lumbar neuronal responses to noxious thermal (52 degrees C, 12 s) stimulation of the hindpaw were recorded before and every 2 min (up to 13 min postinjection) after administration of etomidate. The responses at peak effect of etomidate (as a percentage of the control response) were 63% +/- 16%, 63% +/- 16%, 38% +/- 25%, 36% +/- 30%, and 41% +/- 26% for the 0.125, 0.25, 0.5, 1 and 2 mg/kg doses, respectively. The responses quickly recovered, usually by the 10-min period postinjection. Similar responses were obtained in decerebrate, isoflurane-free rats administered etomidate and in isoflurane-anesthetized rats administered propofol. These data demonstrate that etomidate depresses spinal cord neuronal responses to noxious stimulation and is a possible mechanism by which this drug might produce analgesia.

Facilitation of ischemia-induced release of dopamine and neuronal damage by dexamethasone in the rat striatum.

Glucocorticoids have been reported to aggravate ischemia-induced neuronal damage in both humans and experimental animals. Because an excess release of neurotransmitters is closely related to the outcome of ischemic neuronal damage, we evaluated the effects of dexamethasone on monoaminergic release and histological outcome. Changes in the extracellular concentrations of monoamines and their metabolites in the striatum produced by occlusion of the middle cerebral artery for 20 min were measured using a microdialysis high-performance liquid chromatography procedure, and the effects of intracerebroventricular administration of dexamethasone (10 microg) were evaluated in halothane-anesthesized rats. The histological outcome was evaluated by light microscopy 7 days after ischemia. Additionally, the effects of lesioning of the substantia nigra were estimated. The extracellular concentrations of neither dopamine nor serotonin were affected by the administration of dexamethasone in the nonischemic state. The occlusion of the middle cerebral artery produced a marked increase in the extracellular concentration of dopamine in the striatum, the peak value being 240 times that before ischemia. The preischemic administration of dexamethasone enhanced the increase in dopamine level during ischemia, and the peak value in the dexamethasone group was 640% of that in the vehicle group. After 7 days, ischemic neuronal damage in the dexamethasone group was severe compared with that in the vehicle group. In rats receiving the substantia nigra lesion, the ischemic release of dopamine was abolished, and the aggravation of ischemic neuronal damage by dexamethasone was completely alleviated. Changes in the release of monoamines may be a contributing factor in the development of the ischemic neuronal damage induced by glucocorticoids.