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Nortriptyline has been shown to be a potent antagonistof the platelet serotonin transporter, whichmodulates platelet aggregation response with remarkable reliance on hemostasis.The present alternative was designed to investigate the antihyperalgesic and anti-inflammatory effectof nortriptyline in a carrageenan induced paw edema model, as well as to examine whether the antihyperalgesic and anti-inflammatory responses are mediated by its mechanism of action. Norantipyrine, a standard and type I of mechanism of action of nortriptyline,was used to compare the antihyperalgesic effect of nortriptyline with that of norantipyrine. The anti-inflammatory effect of nortriptyline was evaluated by measuringthe myeloperoxidase (MPO) activity in the lavage fluid of the paw edema and leukocytes infiltration induced by carrageenan.Nasal administration of carrageenan was used for inducing paw edema. Pre-treatment with nortriptyline and norantipyrine evoked a significant inhibition oflipid peroxidation in liver and kidney homogenates without changing the enzymatic activities of GST, GPx and GR. Pre-treatment with nortriptyline also had no effect on the enzymatic activitiesof GST, GPx and GR in leukocytes. Nortriptyline and norantipyrine inhibited the carrageenan induced paw edema by 55 ± 2.91, 40 ± 1.23% and 37 ± 1.28% on the1st, 2nd and 3rd day respectively. Nortriptyline and norantipyrine also reduced the frequency and force of pawwithdrawal significantly (p < 0.05 and 0.01, respectively). Pre-treatment with nortriptyline and norantipyrine inhibitedleukocyte migration to carrageenan-treated skin significantly (p < 0.001 and p < 0.01, respectively). The reduction of MPO activity in theleukocyte lavage in carrageenan induced paw edema in pre-treated animals was 15.67 ± 6.62, 13.64 ± 7.78 and 13.33 ± 7.48%,respectively. d2c66b5586