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.
Ho
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Department of Pharmacology, Medical School, University of Minnesota, Minneapolis.
Takemori
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D004361:Drug Tolerance; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects; D017473:Receptors, Opioid, kappa; D012701:Serotonin / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*
D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D012701:Serotonin; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002118:Calcium