Amitriptyline and Acute Inflammation: A Study Using Intravital Microscopy and the Carrageenan-Induced Paw Edema Model

Abstract

Background/Aims: Antidepressants are reported to exhibit antiinflammatory effects. However, mechanisms involved in this action have not been elucidated. Thus, the objectives of the present study were (a) to evaluate the effects of amitriptyline on the acute inflammatory process, and (b) to investigate the participation of α₁-adrenergic receptors and glucocorticoids as possible mechanisms implicated in the amitriptyline action on inflammation. Methods and Results: Single and multiple doses of amitriptyline were administered to rats submitted to the carrageenan-induced paw edema model. The results showed a significant antiedematous reaction to amitriptyline, mainly when administered at each elimination half-life. The next step was to evaluate its effects on leukocyte behavior, using intravital microscopy. Amitriptyline produced a significant effect on leukocyte behavior. To investigate possible mechanisms involved, a glucocorticoid receptor antagonist (RU-486) and an α₁-adrenergic receptor antagonist (prazosin) were used. RU-486 administration lacked the ability to decrease the amitriptyline antiinflammatory effects in the carrageenan-induced paw edema model. Prazosin pretreatment potentiated the amitriptyline antiinflammatory effect without presenting an effect per se. Conclusion: The present study shows the ability of amitriptyline to decrease edema and affect leukocyte behavior in an acute inflammatory process; and, for the first time to our knowledge, we suggest the involvement of α₁-adrenoceptors in the antiinflammatory effects of amitriptyline.

Amitriptyline, clomipramine, and maprotiline attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation

“…4,8,[13][14][15][16] In all cases, these agents were given intraperitoneally, which partially explains the lower doses injected. In general, long-term treatment of patients with antidepressants involves oral administration.…”

“…8,[13][14][15][16] Despite progress regarding the mechanisms involved in the anti-inflammatory effect of these drugs, some questions remain to be It is well known that the edematogenic effects of carrageenan and dextran occur through different pathways. 19 A biphasic inflammatory response due to carrageenan injection has been suggested, 20 with the participation of several inflammatory mediators, including prostaglandins, bradykinin, and serotonin, 21 cytokine production by resident macrophages, and neutrophil migration to the lesion site.…”

“…Regarding carrageenan, our findings are in accordance with other studies. 8,[13][14][15][16] However, to the best of our knowledge, this is the first report of a protective effect of the tested drugs against dextran-induced edema.…”

“…[2][3][4][5][6] Furthermore, it has been reported that heterocyclic antidepressants are able to modulate the immune system. [7][8][9] In addition, a clear reciprocal effect between inflammatory mediators and development of depression is even more evident. [10][11][12] Since these reports, there has been growing research interest in the acute and chronic anti-inflammatory potential of these drugs.…”

“…[10][11][12] Since these reports, there has been growing research interest in the acute and chronic anti-inflammatory potential of these drugs. 8,[13][14][15][16] Current studies on the anti-inflammatory effects of cyclic antidepressants are mainly based on the model of carrageenan-induced paw edema, 8,[13][14][15][16] and considerable progress has been achieved in this area of research. However, further investigation regarding the mechanisms involved in the anti-inflammatory activity of heterocyclic antidepressants is still needed.…”