Release by U-50,488H of [3H]serotonin from brain slices and spinal cord synaptosomes of U-50,488H-tolerant and nontolerant mice.

The effect of U-50,488H [trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl) benzeneacetamide] on the release of [3H] serotonin from mouse brain slices and spinal cord synaptosomes was studied using a superfusion system. Release was stimulated with 30 mM K+ while superfusing with Krebs-Ringer buffer, in the presence or absence of U-50,488H (3 nM to 1 microM). In both tissues, U-50,488H resulted in a concentration-related increase in release. The estimated EC50 values were found to be 14 and 42 nM in brain and spinal tissues, respectively. The increase in release was antagonized by 3 x 10(-7) M naloxone. The induction of release was found to be a Ca+(+)-dependent process which was significantly reduced in Ca+(+)-free medium containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Tolerance to U-50,488H was induced in mice using a slow release method. They were tested with the tail-flick assay to ensure tolerance had developed. The U-50,488H-induced release of [3H] serotonin was observed to decrease from both tissues of the U-50,488H-tolerant animals. These findings suggest that tolerance to the antinociceptive action of U-50,488H is accompanied by a decrease in its ability to stimulate serotonin release from brain and spinal tissues.