The electroreceptor organ of the catfish, Ictalurus melas, as a model for cisplatin-induced ototoxicity.

The ototoxic side-effects of the anti-cancer drug cisplatin (cis-diaminedichloroplatinum) have been widely investigated. However, the exact site of action remains unclear. In this study, the electroreceptor organ of the freshwater catfish Ictalurus melas is used as a model for examining the acute effects of cisplatin. The sensory cells in the electroreceptor organ are homologous to the inner hair cells in the cochlea of mammals. The effects of cisplatin administration can be investigated by in vivo recording of the spike trains from the electroreceptor organ primary afferents. Exposure of electroreceptor organs to 330 microM cisplatin for 1 h causes the spontaneous activity to drop, the overall sensitivity to diminish and the shape of the frequency characteristics to change. These effects persist in the week after administration. Control levels have returned at day 22. These results demonstrate an acute and, with considerable hysteresis, reversible cisplatin effect on the electroreceptor organs, which is to a large extent consistent with the cisplatin-induced effects in isolated hair cells in mammals. The time-course of the effect supports the hypotheses that ion channels are blocked immediately by cisplatin administration, and that cisplatin metabolites disturb enzymatic cellular processes.

Cisplatin ototoxicity and the possibly protective effect of alpha-melanocyte stimulating hormone.

It is known that adrenocorticotrophic hormone (ACTH)-derived peptides, the so-called melanocortins, can reduce cisplatin-induced neurotoxicity. Recently, our group has found that cisplatin-induced ototoxicity can also be reduced or prevented by treatment with the synthetic melanocortin-like peptide, ORG 2766 (Hamers et al., 1994; De Groot et al., 1997). The present study was designed to investigate the possibly ameliorating effects of the physiologically more relevant naturally occurring neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) upon cisplatin ototoxicity and to compare its protective effects to those of ORG 2766. For eight consecutive days guinea pigs were treated with cisplatin at a concentration of either 1.5 mg/kg/day or 2 mg/kg/day. Animals were co-treated with either alpha-MSH (75 microg/kg/day), ORG 2766 (75 microg/kg/day), or a sham injection containing physiological saline. Electrocochleography and hair cell counts were performed. Treatment with 1.5 mg/kg/day cisplatin resulted in a large variability of the morphological and electrophysiological data, a variability that might have masked possible effects of ORG 2766 and alpha-MSH. Treatment with 2 mg/kg/day cisplatin caused less variable, severe reductions in the compound action potentials and cochlear microphonics combined with basal and middle-turn outer hair cell loss in five out of six animals. However, in the alpha-MSH co-treated groups, two out of six animals could be classified as normal, two animals as moderately affected and two animals as severely affected. In the ORG 2766 co-treated group we found three animals that were not affected and three animals that were severely affected. We conclude that the protective effects of alpha-MSH and ORG 2766 co-treatment are comparable and that alpha-MSH might be clinically useful in protecting against cisplatin-induced ototoxicity.

The effect of hyperosmotic treatment on the functioning of ampullary electroreceptor organs.

The condition of the microvilli of the apical membrane in ampullary electroreceptor organs of the freshwater catfish, Ictalurus nebulosus, was manipulated by administration of hyperosmotic solutions (500 mM) in order to investigate to what extent the apical surface area determines the sensitivity and the shape of the frequency curves. Electrophysiological recordings demonstrated that hyperosmotic sucrose and glucose solutions reduce the sensitivity by 80%, and alter the shape of the frequency curves. The synaptic delay and the average spontaneous activity remained almost unchanged. Calculations with an equivalent electric circuit of an electroreceptor cell indicate that a reduction in apical surface area can account for these effects. Apparently, the sensitivity and the frequency curves in ampullary organs in freshwater catfish depend on the apical surface area. A hyperosmotic urea solution proved to be less suitable to investigate the effect of manipulations of the apical surface area. The almost total loss in sensitivity caused by administration of urea is caused by both shunting of the stimulus by leaky tight junctions and a reduced synaptic efficacy. The repetitive activity observed after exposure to glucose or sucrose must be attributed to malfunctioning of postsynaptic parts of the receptor organ.

Vincristine disturbs spontaneous firing of the afferent nerve fibre in ampullary electroreceptor organs.

Ampullary electroreceptor organs of the catfish were apically exposed to 0.3 mM vincristine in order to investigate the part played by the microtubular system in stimulus transduction. The main effects were repetitive firing of the afferent fibre, a reduction of the mean spontaneous activity and a reduction of the spike amplitude two to four days after exposure to vincristine. The mean sensitivity was less susceptible to vincristine than the spontaneous activity. Since the shape of the frequency curves remained unchanged and similar effects as described above were also observed after denervation, we conclude that vincristine most likely does not affect electroreceptor cell functioning, but causes degeneration of the afferent fibre.

Dynamics of background adaptation in Xenopus laevis: role of catecholamines and melanophore-stimulating hormone.

The pars intermedia of the pituitary gland in Xenopus laevis secretes alpha-melanophore-stimulating hormone (alpha-MSH), which causes dispersion of pigment in dermal melanophores in animals on a black background. In the present study we have determined plasma levels of alpha-MSH in animals undergoing adaptation to white and black backgrounds. Plasma values of black-adapted animals were high and decreased rapidly after transfer to a white background, as did the degree of pigment dispersion in dermal melanophores. Plasma MSH values of white-adapted animals were below the detection limit of our radioimmunoassay. Transfer of white animals to a black background resulted in complete dispersion of melanophore pigment within a few hours, but plasma MSH levels remained low for at least 24 hr. This discrepancy between plasma MSH and degree of pigment dispersion suggested the involvement of an additional factor for stimulating dispersion. Results of in vitro and in vivo experiments with receptor agonists and antagonists indicated that a beta-adrenergic mechanism, functioning at the level of the melanophore, is involved in the stimulation of pigment dispersion during the early stages of background adaptation.