Mast cells mediate allergies, hypersensitivities, host defense, and venom neutralization. An area of recent interest is the contribution of mast cells to inflammatory pain. Here we found that specific, local activation of mast cells produced plantar hyperalgesia in mice. Basic secretagogue compound 48/80 induced plantar mast cell degranulation accompanied by thermal hyperalgesia, tissue edema, and neutrophil influx in the hindpaws of ND4 Swiss mice. Blocking mast cell degranulation, neutrophil extravasation, and histamine signaling abrogated these responses. Compound 48/80 also produced edema, pain, and neutrophil influx in WT C57BL/6 but not in genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice. These responses were restored following plantar reconstitution with bone marrow-derived cultured mast cells.

Neosugar, a fructooligosaccharide mixture, was tested for genotoxicity in three assays:(1) microbial reverse mutation assays in Salmonella typhimuriyn (Ames assay) and Eschericliia coli WP2 uvrA, (2) the L5178Y mouse lymphoma TK mammalian cell mutation assay, and (3) an assay for the induction of unscheduled DNA synthesis (UDS) in human epithelioid cells (HeLa S3). Each assay was conducted at a wide range of dose levels, both with and without metabolic activation. Test results gave no indication that neosugar possessed any genotoxic potential. The carcinogenicity and chronic toxicity of neosugar were examined in Fischer 344 rats. Rats were fed diets containing 0, 8000, 20,000, or 50,000 ppm neosugar for 104 weeks. No dose-related effects on survival, growth, hematology, blood chemistry, organ weights, or nonneoplastic lesions were observed. The incidence of rare and spontaneous tumors was comparable between control and neosugar treatment groups, with the exception of pituitary adenomas in male rats. In light of the background incidence of this tumor and an equivocal dose-response trend, it is unlikely that neosugar treatment is related to the incidence of pituitary adenomas in male rats. The results of this study indicate that neosugar is nonmutagenic and that rats are not adversely affected by chronic neosugar exposure.-TOXICOLOGICAL EVALUATION OF NEOSUGAR pg/p:late in each tester strain, with and without metabolic activation, using procedures complying with OECD and Japanese Ministry of Health and Welfare guidelines. Three test plates per strain per tireatment condition were used. Appropriate negative and positive controls were used with each strain. The positive controls used in the absence of metabolic activation were N-ethyl-N'-nitro-Nnitrosoguanidine with T A 1535, TA 100, and E. coli WP2 uvrA, 2-nitrofluorene with TA 98 and TA 1538, and 9-aminoacridine with TA 1537. With metabolic activation, 2-aminoanthracene was used with all strains.Mmnmalian cell mutation assay. Mouse lymphoma L5178Y cells (3.7.2~) were obtained from Dr. .J. Cole, Sussex University. The cells, which are heterozygous at the thymidine kinase locus (TK ") were grown routinely as suspensions in roller culture in sodium bicarbonate-buffered RPMI 1640 medium supplemented with sodium pyruvate (1 10 pg/ml), pluronic F68 (1 mg/ml), gentamicin (50 pg/ml), and 10% heat-inactivated horse serum, in an atmosphere of 5% CO, in air. For cloning, the serum content of the medium was doubled to 20%, the pluronic content reduced to 0.2 mghnl, and 0.3% Noble agar was incorporated. Chemical treatment of the cells took place in hepes-buffered RPMI 1640 medium without added serum, pluronic, or sodium pyruvate.Preliminary toxicity tests were conducted by treating cells in suspension with neosugar at 50, 100, 250, 1000, 2500, and 5000 pg/ml at 37°C for 3 hr. The highest dose used represented the maximum dose used routinely in this assay to avoid confounding physical effects. The cells were then washed and resuspended in normal growth medium and cultured at 37°C...

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