Summary
The main purpose of these experiments was to compare the effects of methadone and morphine on cerebral 5-hydroxytryptamine (5-HT) synthesis and 5-hydroxyindoleacetic acid (5-HIAA) formation. In addition the rate of catecholamine synthesis and the concentrations of tyrosine and tryptophan in the brain were measured, as well as the effects of naloxone were investigated.
Morphine (34 mg/kg, 2h) increased the synthesis of 5-HT and catecholamines, determined by measuring the accumulation of 5-hydroxytryptophan (5-HTP) and dopa in the whole brain of rats treated with an inhibitor of the aromatic l-amino acid decarboxylase (3-hydroxybenzylhydrazine hydrochloride, NSD 1015). Morphine also increased the cerebral 5-HIAA concentration both in rats treated with NSD 1015 or probenecid. Naloxone antagonized all these effects of morphine. A lower dose of naloxone was needed to antagonize the effect of morphine on 5-HT than on catecholamine synthesis, Similarly to morphine methadone (9 mg/kg, 2 h) increased the cerebral 5-HIAA concentration, but methadone alone did not alter the rate of formation of 5-HTP. However, in combination with naloxone methadone decreased the concentration of 5-HIAA and the accumulation of 5-HTP depending both on the dose of methadone and that of naloxone. Similarly to morphine, methadone stimulated and never reduced the catecholamine synthesis; naloxone antagonized this effect. Both morphine and methadone increased the cerebral concentrations of tryptophan and tyrosine and naloxone antagonized these effects. In addition naloxone alone (2+2 mg/kg, 1+2h) decreased the cerebral tyrosine concentration significantly suggesting that the opiate receptors are involved in the control of cerebral tyrosine concentration.
Our results suggest that methadone similarly to morphine stimulates the cerebral 5-HT and catecholamine synthesis, and that these effects are most probably mediated via opiate receptors. However, when opiate receptors are blocked, methadone is able to decrease the cerebral 5-HT synthesis and cerebral 5-HIAA concentration probably via a feedback mechanism produced by blockade of 5-HT reuptake.
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Ahtee, L., Carlsson, A. Dual action of methadone on 5-HT synthesis and metabolism. Naunyn-Schmiedeberg's Arch. Pharmacol. 307, 51–56 (1979). https://doi.org/10.1007/BF00506551
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DOI: https://doi.org/10.1007/BF00506551