Efeito analgésico da melatonina em um modelo animal da síndrome de dor complexa regional tipo I

Abstract

Complex regional pain syndrome-type I (CRPS-I) affects upper or lower limbs distal parts, leading symptoms like chronic pain, edema, trophic changes and motor function abnormalities. This syndrome commonly follows factures and sprains. The pathophysiology of CRPS-I is not completely understood and its suggested that microvessels changes related to the syndrome maintenance lead to a reduction in oxygen supply. In this study the objective was to evaluation the time course of the antinociceptive activity of melatonin, an endogenous indolamine released mainly by pineal gland, in the mechanical and cold hypersensitivity and in the edema presented in the chronic post-ischemic pain (CPIP) in mice; an animal model of human CRPS-I, and participation of MT1/MT2 receptors and oxidative stress in this model. The antinociceptive activity of melatonin in the nociception evoked by TRPs (transient receptors potential) and ASICs (acid-sensing ion channels). CPIP was induced in Swiss male mice by placing a tourniquet proximal to the ankle joint for 3 hours, followed by removal to allow tissue reperfusion. The mechanical (0.4 g von Frey filaments) and cold (cold plate 4 ºC) hypersensitivity was mensured on second and seventh days after reperfusion. Catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GPx) enzyme activity and malondialdehyde (MDA) levels were measured 2 h, 2 and 7 days after reperfusion, tissues were collected 30 min after melatonin treatment (100 mg/kg, i.p.). Melatonin activity (10 – 100 mg/kg, i.p., or 10 – 100 ng/paw, i.pl.) was also evaluated by measuring of nociception evoked by TRPV1 agonists (capsaicin, 30,5 ng/paw, i.pl.), TRPA1 (cinnamaldehyde, 1,32 μg/paw), TRPM8 (menthol, 1.2 μg/paw) and ASICs (acetic acid 2%, pH 1.98). The treatment with melatonin (10-100 mg/kg, i.p.) dose-dependently reduced the mechanical hypersensitivity 2 and 7 days after reperfusion and with 100 mg/kg the effect remained by for up 2 h after administration. Furthermore, the treatment with melatonin (100 mg/kg, i.p.) also reduced the cold hypersensitivity 2 and 7 days after reperfusion. However, the melatonin effect (100 mg/kg) was not affected by pretreatment with luzindole (10 mg/kg, i.p., non-selective MT1/MT2 antagonist). The melatonin (100 mg/kg, i.p.) also reduced the edema evoked by CPIP in the second day after reperfusion. GR enzyme activity was reduced 2 h after reperfusion and melatonin treatment didn´t change this parameter. GR and GPx, and, Cat and GPx enzymes activities were elevated on days 2 and 7, respectively, and melatonin reversed this increase. The systemic administration (i.p.) of melatonin inhibited the nociception evoked by capsaicin, cinnamaldehyde, menthol and acid saline, inhibitions of 63 + 16%, 41 + 13%, 62 + 10% e 47 + 12%, respectively. Moreover, the peripheral administration of melatonin only inhibited the nociception evoked by capsaicin (49 + 6%) and cinnamaldehyde (60 + 6%). In conclusion, this study extends the literature and shows that melatonin is able to reduce the mechanical and thermal hypersensitivity and the edema in the CPIP model, probably by a modulation of redox status of the cell through its antioxidant properties and inhibition of peripheral nociceptors.