Int J Neuropsychopharmacol. 2005 Jun 20;:1-9.
Amitriptyline and nortriptyline inhibit interleukin-1beta and tumour necrosis factor-alpha release by rat mixed glial and microglial cell cultures.

Obuchowicz E, Kowalski J, Labuzek K, Krysiak R, Pendzich J, Herman ZS.

Department of Clinical Pharmacology, Silesian University School of Medicine, Katowice, Poland.

Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

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Eur J Pharmacol. 1990 Jan 25;176(1):69-74.
Amitriptyline-induced morphological alterations of the rat blood-brain barrier.

Sarmento A, Albino-Teixeira A, Azevedo I.

Laboratorio de Farmacologia, Faculdade de Medicina do Porto, Portugal.

Amitriptyline is known to increase the permeability of the blood-brain barrier but the morphological basis of this increase has not been studied. As catecholamines can influence pinocytosis in dog peripheral blood vessels, the effect of amitriptyline on the pinocytotic activity of blood brain microvessels was studied. Amitriptyline, 34 mg.kg-1 i.p., was injected to rats and the parietal cortex of control and treated animals was prepared for ultrastructural study. Pinocytotic vesicles in endothelial cells were quantified. Amitriptyline significantly increased the density of pinocytotic vesicles in capillary endothelial cells. No other morphological changes occurred after amitriptyline treatment. We conclude that the increase in blood-brain barrier permeability due to amitriptyline may be ascribed at least in part to an increase of pinocytotic activity in brain capillary endothelial cells.

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Ann Neurol. 1983 Feb;13(2):160-4.
Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system.

Botney M, Fields HL.

Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.

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Ciba Found Symp. 1979;(74):157-66.
Adrenergic and serotonergic mechanisms in depression and their response to amitriptyline.

Coppen A, Wood K.

Our investigations into the chemical pathology of the affective disorders have indicated that depressed patients not only have significantly reduced rates of accumulation of 5-hydroxytryptamine (5-HT) into their blood platelets but their peripheral alpha-adrenoreceptors are supersensitive. Investigations into the mode of action of amitriptyline have centred on these abnormal adrenergic and serotonergic mechanisms in depressed patients. We have not detected any significant relationship between blood platelet 5-HT re-uptake inhibition and therapeutic response to amitriptyline in depressed patients, although there is a significant correlation with plasma levels of the drug. It is interesting to note that nortriptyline, the major metabolite of amitriptyline, blocks the alpha-adrenoreceptor but the degree of blocking of this supersensitive receptor is significantly correlated to poor outcome. Amitriptyline does not appear to correct these abnormal mechanisms in depressed patients. These results are discussed with reference to other pharmacological actions of amitriptyline and other antidepressant drugs.

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Neuropharmacology. 1987 Jun;26(6):531-9.
Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline.

Hamon M, Gozlan H, Bourgoin S, Benoliel JJ, Mauborgne A, Taquet H, Cesselin F, Mico JA.

The central mechanism responsible for the potentiation by antidepressant drugs of analgesia induced by morphine, was explored by measuring the levels of various neuropeptides (met-enkephalin, leu-enkephalin, dynorphin, substance P and cholecystokinin-like materials) and the density of delta and mu opioid binding sites in the spinal cord of rats treated for 14 days with amoxapine (10 mg/kg i.p., daily) or amitriptyline (10 mg/kg i.p., daily). Similar measurements were made in the hypothalamus and cerebral cortex for comparison. Chronic treatment with amoxapine or amitriptyline did not affect the levels of dynorphin, substance P and cholecystokinin, but markedly enhanced the levels of leu-enkephalin in the three structures examined. The levels of met-enkephalin were also increased after treatment with amitriptyline but only in the spinal cord and hypothalamus. No changes in opioid receptors were found in the cerebral cortex, but the densities of delta and mu opioid binding sites were increased in the spinal cord, and decreased in the hypothalamus of rats treated with amoxapine or amitriptyline. These changes induced by antidepressants in opioidergic markers at the spinal level might account for the potentiation of the action of morphine in amoxapine- or amitriptyline-treated rats. In addition, the observed alterations in the same markers in the hypothalamus could be associated with changes induced by antidepressants in neuroendocrine regulation.

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Pharmacol Toxicol. 1987 Nov;61(5):342-6.
Formation of a quaternary N-glucuronide of amitriptyline in human liver microsomes.

Dahl-Puustinen ML, Bertilsson L.

Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.

Amitriptyline N-glucuronide was isolated from urine of a patient treated with therapeutic doses of amitriptyline. The glucuronide was hydrolyzed by hot alkaline treatment and, to a lesser degree, by treatment with beta-glucuronidase. A method for the direct measurement of amitriptyline glucuronide by HPLC was developed. Human liver microsomes were shown to glucuronidate amitriptyline in the presence of UDPGA, and the activity varied 7-fold among microsomes from 13 different human livers. The glucuronidation of amitriptyline was inhibited by p-nitrophenol but not by morphine. E-10-hydroxynortriptyline, a major metabolite of amitriptyline, had only a slight inhibitory effect on the glucuronidation of amitriptyline. No significant correlation was found between the glucuronidation of amitriptyline and that of E-10-hydroxynortriptyline in the microsomes studied.

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Pharmakopsychiatr Neuropsychopharmakol. 1980 May;13(3):111-6.
On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients.

Jungkunz G, Kuss HJ.

The antidepressant effect of amitriptyline was studied in 28 endogenous depressive patients. They received 150 mg amitriptyline once nightly in a sustained release form for 4 weeks. Blood samples were drawn 12 hrs. after medication. Amitriptyline concentrations were between 35--300 ng/ml Nortriptyline concentrations were between 20--330 ng/ml. No correlations were found between plasma concentrations of amitriptyline, nortriptyline, or their sum, and the clinical outcome of treatment. Plasma levels of amitriptyline depended on neither the age nor the sex of the patients. A significant correlation was found between the ratio of nortriptyline to amitriptyline concentrations in serum (demethylation ratio) and clinical improvement. The demethylation ratio appeared to be relatively constant after a few days of treatment. The results suggest that monitoring the demethylation ratio of endogenous depressive patients treated with amitriptyline may predict therapeutic effects of the treatment. They also suggest that a balance between noradrenergic and serotonergic mechanisms is necessary to improve antidepressant treatment with amitriptyline.

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Arzneimittelforschung. 1986 Mar;36(3):460-3.
Comparison of some effects of paroxetine with amitriptyline on the cardiovascular system in animals.

Hamilton TC, Norton J, Poyser RH, Thormahlen D.

The effects of intravenous infusions of paroxetine, a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, amitriptyline, on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, paroxetine was less cardiotoxic than amitriptyline in both species. Thus, paroxetine has the advantage over amitriptyline of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than amitriptyline in tests for antidepressant activity.

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