Our results indicate that release of histamine from mast cells after stimulation with NGF is regulated by tyrosine kinase, PLC, PI-3 kinase and PKC, but not by MAP kinases. This biochemical pathway differs from that provoked by compound 48/80.
Psychotropic agents modify the release of histamine and serotonin from rat peritoneal mast cells induced by compound 48/80. Some antidepressants, such as clomipramine and fluoxetine (10(-8) - 10(-5) mol/l), increase the percentage of released serotonin in the incubation medium but have no effect on histamine release. In contrast, amitriptyline (10(-4) mol/l) inhibits the secretion of histamine and permits that of serotonin. The varying effects of antidepressants on the secretion of histamine and serotonin could be explained either by a differential mechanism of secretion of both amines from mast cells or by a selective effect of drugs on the reuptake of serotonin into mast cells after stimulation by compound 48/80. These hypotheses were further investigated in our present study on rat peritoneal mast cells. Our findings suggest that antidepressants influence the secretion and the reuptake process of amines used. Their effects depend on the concentration of the drug. At lower concentrations, antidepressants (amitriptyline, doxepine and clomipramine) produce no effect on the secretion of the amines whereas at higher concentrations ( > 10(-5) mol/l), they inhibit the release. Additionally, mast cells are capable of removing released serotonin from the incubation medium. Serotonin uptake is an active process which increases with the time of incubation with exogenous serotonin and depends on the presence of extracellular Ca2+ and on the temperature of the medium. Preincubation of mast cells with antidepressants inhibits the reuptake of serotonin into mast cells and thus increases the concentration of serotonin in the incubation medium. Since the reuptake of serotonin is a relatively slow process, the elevation of serotonin in the medium is evident only after longer times of incubation.
1 The activity of the Na+/K+-pump in rat peritoneal mast cells was measured at various time intervals after induction of cellular histamine release by compound 48/80 or by the antigen-antibody reaction. The Na+/K+-pump activity was assessed as the ouabain-sensitive potassium uptake of the cells using 6 Rb+ as a tracer for potassium (K+(86Rb+)-uptake).
The involvement of serotonin (5-HT) in chronic pain mechanisms is established. 5-HT inhibits central painful stimuli, but recent data suggests that 5-HT could also enhance pain stimulus from the periphery, where mast cells play an important role. We aimed in our study to clarify the influence of selected tricyclic antidepressants (TCAs) on mast cell function: secretion, uptake, and reuptake of 5-HT, that could interfere with 5-HT levels and in this way contribute to the generation of pain. As an experimental model, we used isolated rat peritoneal mast cells and incubated them with selected TCAs (clomipramine, amitriptyline, doxepin, and imipramine) under different experimental conditions. 5-HT release, uptake, and reuptake were determined spectrofluorometrically. We showed that TCAs were able to inhibit 5-HT secretion from mast cells, as well as uptake of exogenous 5-HT and reuptake of secreted 5-HT back into mast cells. The effects of TCAs were concentration dependent; higher concentrations of TCAs inhibited the secretion of 5-HT induced by compound 48/80, whereas lower concentrations of TCAs inhibited 5-HT uptake. The most effective TCA was halogenated clomipramine. As TCAs are well introduced in chronic pain treatment, the insight into mechanisms of action is important for an understanding of their effect in various pain conditions.
The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives. Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials. Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used. Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. g. severe central nervous system depression, are more pronounced in children than in adults. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority. Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale."
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