Psychopharmacology
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The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha 2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10 micrograms/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. ⋯ This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha 2-adrenergic antagonist, atipamezole, 10-50 micrograms/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha 1-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha 2-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.
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Clinical Trial Controlled Clinical Trial
Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans.
The effects of depletion of the serotonin precursor, L-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. ⋯ In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.