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The origin of nociception alteration in rats treated with betacytotoxic drugs: comparison of hot plate and paw pressure test

THE ORIGIN OF NOCICEPTION ALTERATION IN RATS TREATED WITH BETACYTOTOXIC DRUGS ; COMPARISON OF HOT PLATE AND PAW PRESSURE TEST Melita Šalković-Petrišić, Ivana Ferber and Zdravko Lacković Department of Pharmacology, Medical School and Croatian Institute for Brain Research, University of Zagreb, Šalata 11, 10 000 Zagreb, Croatia Betacytotoxics alloxan and streptozotocin are widely used drugs for induction of experimental diabetes mellitus in rats following peripheral administration of high doses, due to their selective toxicity for insulin producing/secreting cells. Diabetes mellitus is often accompanied by diabetic neuropathy and altered nociception, usually assumed to be a consequence of the peripheral abnormalities. However, recent literature data suggest involvement of the central nervous system, as well. Rats treated intracerebroventricularly (icv) with low doses of betacytotoxic drugs do not get diabetes mellitus, but develop the state of so called “ cerebral diabetes” manifested with similar brain neurochemistry and cognitive alterations as those seen in diabetes mellitus. In line with that and the existence of brain insulin system and betacytotoxics selectivity for insulin producing/secreting cells, betacytotoxic icv – treated rats present a good experimental model for investigating the central origin of diabetes related abnormalities. We have investigated the spontaneous pain threshold by means of two different tests (hot plate and paw pressure test) in rats treated with two betacytotoxic drugs (alloxan and streptozotocin) following their peripheral, diabetogenic and central, nondiabetogenic administration. Four weeks following the drug treatment, the spontaneous pain threshold, determined as a reaction latency time in the hot plate test was increased in alloxan (+52%)- and streptozotocin (+100%)-diabetic rats. Similar, but less pronounced increase was also observed in the hot plate test in alloxan (+46%) and streptozotocin (+62%) icv-treated rats. However, the spontaneous pain threshold, determined as a reaction latency time in the paw pressure test was decreased in alloxan (-45%)- and streptozotocin (-31%)-diabetic animals, as well as in alloxan (-28%)- and streptozotocin (-23%) icv-treated ones, in comparison to the respective control animals. Alloxan and streptozotocin have different mechanisms of action. Therefore, the similarity of the effects they induce, and moreover, the similarity of their effects after peripheral, diabetogenic and central, nondiabetogenic administration, suggest that the observed nociception alterations induced by these drugs are not the consequence of their nonspecific toxic effects. Furthermore, the presented results support the hypothesis that alloxan- and streptozotocin-induced alterations of nociception might be of a central origin and not related to the beta cell destruction. However, it seems that betacytotoxic drugs differently affect nociception induced by thermal and mechanic noxa, the molecular mechanism of which remains to be discovered. Supported by the projects of the Croatian Ministry of Science and Technology (0108253 and 108134).

nociception; streptozotocin; alloxan

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