STUDIES ON THE DEVELOPMENT OF TOLERANCE AND POTENTIAL SPINAL NEUROTOXICITY AFTER CHRONIC INTRATHECAL CARBACHOL-ANTINOCICEPTION IN THE RAT

The antinociceptive effect in rats produced by chronic intrathecal administration of carbachol was studied for 14 days by the tail immersion test and the paw compression test. Daily injection of 10 mu-g carbachol intrathecally (lumbar level) to 8 rats produced an increase in latency times lasting from day 1 to day 4. The effect was statistically significant during the first 4 days, but not thereafter in both the tail immersion test and the paw compression test as compared to the rats (n = 6) injected with saline. Histopathological examinations of the lumbar spinal cord by light and electron microscopy revealed no signs of neurotoxic reactions of the neurons, nor the spinal tracts. Quantitative morphometric analyses were made by the "disector method", which is an unbiased stereological estimator of cell number and mean cell volume. In the laminae I-III of the L:1 segment, an average number of 88 000 cells/mm3 was found and the mean cell volume was calculated at 560-mu-m3. Comparison with untreated rats (n = 4) and those injected with saline showed no statistically significant differences. In the present study, the combination of different morphological analyses offers a sensitive method to trace toxic reactions of the nervous tissue. According to these results, intrathecal carbachol produces antinociception, and seems atoxic to spinal nervous tissue, but before intrathecal administration of carbachol to humans is considered, more neurotoxicological data must be obtained.