TOLERANCE TO DRUG-INDUCED WRITHING IN MICE

¹ Departments of Medicine (Diviaion of Clinical Pharmacology) and of Pharmacology and Experimental Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland

This study was done to elucidate the development of tolerance to drug-induced writhing in mice and to seek clues concerning the mechanism of writhing. Tolerance is induced by repeated administration of phenylquinone (PQ) or acetic acid (AA) on successive days. This tolerance is relative and can be overcome by larger doses. Cross-tolerance is demonstrated between the two drugs. Inhibition of writhing with morphine sulfate or sodium salicylate did not inhibit development of tolerance, suggesting that tolerance to nociception induced by PQ or AA arises neither centrally nor in the pain endings. Measurement of sleep time after pentobarbital was the same for 1-day-treated animals that were writhing as for 3-day-treated animals that were no linger writhing, suggesting that PQ is not an enzyme inducer. There is no significant difference in capillary permeability as manifested by plasma-bound dye leakage into the peritoneal cavity between 1-day-treated animals and 3-day-treated animals. Tolerance may be due to an induced decrease in receptors at some point in the release mechanism according to a process suggested by Collier. Assay for serotonin content in the small intestine showed no significant difference between 1-day-treated animals and 3-day-treated animals. Bioassay for "kinin" in peritoneal washings of mice treated with PQ or AA revealed significantly more "kinin" than in washings from uninjected control mice, but there is no statistically significant difference between "kinin" content of peritoneal washings of saline-treated mice and mice that writhed after either PQ or AA. Further, there is no significant difference between mice treated for 1 day and those treated for 3 days with either PQ or AA. In addition, the contraction curves of "kinin" extracted from treated and untreated mice differ significantly from that of authentic bradykinin (BK), in that two separate components are visible in contractions after the former but not the latter. The first "fast" component remains unidentified while the second appears to be similar to BK. Further attempts to identify the "kinin" by using an IRC-50 column failed. Our data do not support the hypothesis that BK alone is the mediator of writhing or that depletion of BK accounts for tolerance. Reversible damage to sensory nerve endings by repeated injections of inciting agent cannot be ruled out as an explanation for the phenomenon described.