A 5-HT3 RECEPTOR ANTAGONIST FAILS TO PREVENT CISPLATIN-INDUCED TOXICITY IN IMMATURE RAT SPINAL-CORD

The use of high doses of cisplatin in treating cancers has been limite d by two major adverse effects - emesis and peripheral neuropathies. T he emesis has become largely controlled by the introduction of a new c lass of drugs - the 5-HT3 receptor antagonists. The current study was undertaken to determine if these drugs would also prevent cisplatin-in duced neuropathy. We have used a developing rat as an animal model and determined the effects of cisplatin on morphology (loss of spinal cor d calcitonin gene-related peptide (CGRP)-containing neurons) and behav ior (gait abnormalities and pain perception). Rat pups from the age of 5 days were treated twice weekly for 4 weeks with cisplatin (1 mg/kg) , the 5-HT3 antagonist MDL 72222 (3 mg/kg) or both. The animals were t ested for pain perception (using tail-flick latencies) at 17 and 21 da ys of age and for a gait abnormality at 24 days of age. At 34 days of age, the animals were perfused and the lumbar region of the spinal cor ds stained immunocytochemically for CGRP. Our results show that cispla tin treatment resulted in a dramatic loss of CORP neurons in the dorsa l horn of the spinal cord and a corresponding increase in the animals' threshold for pain. In addition, the animals showed a pronounced gait abnormality, characterized by 'toeing-in'. Treatment with MDL 72222 n ot only failed to protect against the loss of CGRP neurons but also wo rsened the gait abnormalities seen after cisplatin treatment alone. Th ese studies confirm and extend the list of morphological and functiona l adverse effects of cisplatin treatment. As well, our results raise t he concern that co-administration of a 5-HT, antagonist may potentiate some adverse effects.