Avaliação da neuropatia sensitiva periférica induzida por oxaliplatina em camundongos e do efeito das drogas anticonvulsivantes Gabapentina, Carbamazepina e Oxcarbazepina

Abstract

The antineoplastic drug oxaliplatin that is the third generation of platinum agents and first-line treatment of colorectal cancer, has a frequent and limiting toxic effect: the painful peripheral sensory neuropathy. This condition has an acute onset but can become chronic and irreversible with cumulative doses. Given the few experimental studies and murine models to study this condition, our objectives were to develop a model for the study of peripheral neuropathy induced by oxaliplatin in mice and further evaluate the effect of gabapentin, carbamazepine and oxcarbazepine in this condition. This study was approved by the Ethics Committee on Animal Research of the Federal University of Ceará (Num. 027/08). We used male Swiss mice (20-40g) treated with oxaliplatin (4mg/Kg-1 mg/kg, IV) by 4.5 weeks, along with the evaluation of nociceptive tests weekly. Allodynia and thermal hyperalgesia was tested by immersion of the tail (TIT) in cold water (10 and 4°C, allodynia and hiperalgesia, respectively), or in warm water (42 and 46°C, allodynia and hyperalgesia, respectively). The plantar mechanical hyperalgesia was assessed by electronic von Frey test that consisted of the stimulation of the hind paws of mice with a force sensor (grams) until its removal by a characteristic movement. At the end of experiments, the spinal cords of mice were removed and processed for immunohistochemical evaluation of the expression of c-Fos in the dorsal horn. It was demonstrated that oxaliplatin in the plantar mechanical hiperalgesia test promoted a significant decrease (p <0.001) in the nociceptive threshold from the 14th day. From the 28th day there was no difference among the doses of oxaliplatin, which were all significantly different from group control. In TIT (4°C) there was a significant decrease (p <0.05) in the nociceptive threshold on the 56th day. In the TIT (10°C) was a significant reduction (p <0.001) of the nociceptive threshold in 56th day at all the doses. In the TIT (42°C) it was also observed a reduction of nociceptive threshold at 56th day where the three doses were significantly different from control group (p <0.01 and p <0.05). In the TIT (46°C) it was observed a significant decrease tail withdrawal threshold from the 49th day (p<0.05) in the three doses when compared to the control group. The treatment with gabapentin (6-54 mg / kg), carbamazepine (0.3 to 30 mg / kg), oxcarbazepine (0.3 to 100 mg / kg) increased nociceptive threshold, indicating analgesic effect. The treatment with indomethacin (1-4 mg / kg) showed no analgesic activity in this model. Immunohistochemistry showed an increased expression of c8 Fos in the dorsal horn of the spinal cord of mice treated with oxaliplatin at 56th day, when compared to the control group. We conclude that oxaliplatin induces neurotoxicity that leads to mechanical and thermal hyperalgesia and thermal allodynia and increased expression of c-Fos that seems to be dose-cumulative and time-dependent. Gabapentin, carbamazepine and oxcarbazepine inhibited the already installed allodynia, validating the neuropathic aspect of this neurotoxicity. The study provides methodology for future studies on therapies that may enable the use of oxaliplatin for the treatment of cancer without the peripheral sensory neuropathy that interferes with daily activities of the patients treated.