Autonomic neuropathy induced by cisplatin and vincristine in rats : functional study, electrophysiological and morphological

Introduction: Chemotherapeutic agents are chemical compounds used for the treatment of cancer. The efficacy of chemotherapy is limited by its side effects such as nephro, neuro, hepato and ototoxicity. Cisplatin and vincristine are chemotherapy drugs and their use is limited by peripheral neuropathy with autonomic, sensory and/or motor involvement. Aims: We evaluated the effect of cisplatin and vincristine on the gastric emptying (GE), gastrointestinal (GI) transit of liquid, baroreflex function, thermal and mechanical withdrawal latencies, electrophysiological parameters of sympathetic neurons and morphology of nerve and muscle tissues in rats. Methods: Vincristine sulphate, cisplatin or saline were injected into the tail vein. Cisplatin was administered at doses of 0.5 mg/Kg (5 doses), 1 mg/kg (2-5 doses) or 2 mg/kg (1, 2 or 5 doses) daily and vincristine was administered at the doses of 50 µg/kg (5 doses), 100µg/kg (2-5 doses) or 150 µg/kg (1, 2 or 5 doses) every other day, both drugs administered in male Wistar rats (200-250g). Next day, they were gavage-fed with a test meal (0.5 mg/ml of phenol red in 5% glucose solution) and were sacrificed 10 minutes later. The recovery of phenol red in the stomach and intestine was determined by spectrophotometry. Peak values of basal mean arterial pressure (MAP) and heart rate (HR) after i.v. phenylephrine 5 mg/kg and atropine 0.5 mg/kg were used to evaluate the baroreflex responses. Animals were subjected to hot plate testing to evaluate changes in the thermal pain threshold and for the assessment of mechanical threshold and allodynia, an dynamic plantar aesthesiometer based on the von Frey filament principle was used. Differences were evaluated by One-Way ANOVA with P 250 µg/kg de 54,5-69,3% e este retarde do esvaziamento gástrico não permaneceu após uma semana de interrupção do tratamento com 5 doses de 150 µg/kg de vincristina. Cisplatina também aumentou o ganho do barorreflexo possivelmente pelo aumento da atividade simpática. Bradicardia induzida por fenilefrina foi aumentada sugerindo disfunção simpática e após a infusão de atropina (0,5 mg/kg) as alterações da freqüência cardíaca relacionadas a infusão desta droga foram mais proeminentes nos ratos tratados com cisplatina que no grupo controle. Cisplatina também alterou a excitabilidade de neurônios do gânglio cervical superior e a morfologia de gânglios autonômicos, somáticos e do nervo vago em ratos. Vincristina reforçou a redução da FC induzida pela fenilefrina e atropina. Conclusão: Nossos resultados demonstraram que cisplatina e vincristina induzem neuropatia autonômica com retarde do esvaziamento gástrico, alteração das respostas barorreflexas e aumento do peso colônico. Cisplatina alterou a latência mecânica, mas não a térmica e a neuropatia autonômica precedeu estas alterações. Em ratos tratados com vincristina a neuropatia sensitiva precedeu as disfunções autonômicas