Long-Term Antidepressant Treatment Inhibits Neuropathic Pain-Induced CREB and PLCγ-1 Phosphorylation in the Mouse Spinal Cord Dorsal Horn

The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate–responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal–regulated kinase (ERK_1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury–induced CREB and PLCγ-1 phosphorylation but had no effect on ERK_1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway.     

N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: Behavioral and biochemical analyses in rats

The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N-acetylcysteine (NAC) – a putative precursor of the most important tissue antioxidant glutathione – in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50–100 mg/kg, ip) or IMI (10 mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity — TAC and the superoxide dismutase activity — SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity.     

Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment

Preclinical data indicate the antidepressant activity of zinc and the involvement of the brain-derived neurotrophic factor (BDNF) in this mechanism. The present study investigates the effect of chronic (16 days) combined treatment with zinc (15 mg/kg zinc hydroaspartate) and imipramine (5 mg/kg) in chronic unpredictable stress (CUS) on the BDNF mRNA level in the rat brain. Moreover, serum zinc concentrations were also assessed. CUS induced a significant reduction in the BDNF mRNA level in the hippocampus by 21% but had no effect in the frontal cortex. Repeated treatment with zinc induced a significant increase in the BDNF mRNA level in the hippocampus in the unstressed animals by 12% and as in the chronically stressed animals by 14%, compared to the appropriate controls. Imipramine treatment did not affect this factor. However, combined treatment of zinc and imipramine induced a 12% elevation of the BDNF mRNA level in the stressed but not in the unstressed rats. CUS induced a 19% reduction in the serum zinc concentration, whereas combined treatment of zinc and imipramine reduced this concentration by 24% in the unstressed and increased it (by 20%) in the stressed animals. These results indicate that: 1) CUS induces a reduction in the BDNF gene expression with a concomitant diminution of serum zinc concentration and 2) the CUS-induced reduction in the BDNF gene expression is antagonized by chronic treatment with zinc.     

Imipramine decreases oesophageal pain perception in human male volunteers

Department of Medicine, Suite 501, Pepper Pavilion, Allegheny University Hospitals, Graduate, One Graduate Plaza, 1800 Lombard Street, Philadelphia, Pennsylvania 19146, USA

Correspondence to: Dr D O Castell.

Accepted for publication 19 January 1998

Background—Visceral hyperalgesia is a hallmark of functional gastrointestinal disorders. Antidepressants improve symptoms in these patients, although their mode of action is unclear. Antidepressant, anticholinergic, and analgesic mechanisms have been proposed.
Aims—To investigate whether imipramine, which has a visceral analgesic effect, increases pain thresholds to experimental visceral pain.
Methods—Visceral perception for first sensation and pain was measured with intraoesophageal balloon distension in 15 male volunteers. The effect of imipramine was studied in a double blind, placebo controlled, crossover study. Imipramine was given in ascending doses for 12 days (25 mg days 1-3, 50 mg days 4-6, 75 mg days 7-12), with oesophageal perception studied on day 13. 
Results—Inflation volumes and intraballoon pressures at first sensation were not different between placebo and imipramine. Balloon inflation volume at pain threshold was higher on imipramine (p=0.015). Median intraballoon pressures were not different at pain threshold for placebo and imipramine. Oesophageal wall compliance was not affected by imipramine.
Conclusion—Increased pain thresholds on imipramine in this group of normal male volunteers in the absence of changes in oesophageal tone imply the presence of a visceral analgesic effect.
(GUT 1998;:807-813)

Keywords: antidepressants;  imipramine;  visceral hyperalgesia;  oesophageal balloon;  distension;  functional bowel syndromes

     

Quantitative autoradiographic evidence for axonal transport of imipramine receptors in the central nervous system of the rat

Interruption of the ascending serotonin axons of the medial forebrain bundle (MFB) in the rat brain produced a progressive time-dependent accumulation of imipramine receptors (labeled for autoradiography with [3H]imipramine). The largest accumulation of receptors occurred during the first 12 h at the caudal aspect of the lesion. An electrolytic lesion of the nucleus raphe dorsalis, administered 24 h prior to interruption of the medial forebrain bundle, markedly reduced the number of imipramine receptors on the caudal side of the lesion, while a significant accumulation was still evident on the rostral aspect. These results suggest that imipramine receptors are undergoing the process of orthograde axonal transport to terminals in the forebrain from the neuronal perikarya found in the nucleus raphe dorsalis. These receptors may also be undergoing retrograde transport back to their cell bodies of origin.     

Central noradrenergic adaptation to long-term treatment with imipramine in rhesus monkeys

Rhesus monkeys were treated with the antidepressant drug imipramine; cerebrospinal fluid norepinephrine and dopamine-beta-hydroxylase were measured to assess central noradrenergic activity. Large changes occurred after short-term, but not long-term, treatment. Biochemical stabilization occurs at the time when therapeutic effects are seen in patients.     

Platelet tritiated imipramine binding in psychiatric patients: relationship to symptoms and severity of depression

The clinical and research significance of reduced imipramine binding has remained unclear despite considerable investigation. This study used an assay of demonstrated reliability to investigate the clinical correlates of imipramine binding to platelets in 63 depressed and 33 nondepressed psychiatric patients and 40 healthy control subjects. Both patient groups had Bmax values significantly lower than those of the healthy controls. Unequivocal associations between binding parameters and individual symptoms or groups of symptoms were not established, but a negative correlation between Kd and the number of adverse life events experienced in the preceding 6 months was apparent. These findings provide no support for the view that reduced binding is a trait marker for susceptibility to depression and cast doubt on its specificity as a state marker for the syndrome of depression.     

Adrenoceptor and imipramine receptor binding during the menstrual cycle

The binding characteristics of platelet alpha 2-adrenoceptors, lymphocyte beta 2-adrenoceptors and platelet imipramine receptors were studied in five women during their menstrual cycle. A significant cyclic variation in the number of beta 2-adrenoceptor sites on intact lymphocytes was found during the menstrual cycle, while binding to alpha 2-adrenoceptors and imipramine receptors remained unchanged.     

Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects

Aims The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.
Methods The effect of oral ketoconazole (200  mg day⁻¹ for 14 days) on the kinetics of a single oral dose of imipramine (100  mg) and desipramine (100  mg) was evaluated in two groups of six healthy male subjects.
Results Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16±0.21 to 0.96±0.20  l h⁻¹  kg⁻¹, mean±s.d.; ' of2\P<0.02), a prolongation in imipramine half-life (from 16.7±3.3 to 19.2±5.4  h, ' of2\P<0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507±1707 to 3180±1505  nmol  l⁻¹  h, P <0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.
Conclusions These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N -demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.