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The beta-lactam antibiotic, ceftriaxone, attenuates morphine-evoked hyperthermia in rats.

ABSTRACT: Beta-lactam antibiotics are the first practical pharmaceuticals capable of increasing the expression and activity of the glutamate transporter, GLT-1, in the CNS. However, the functional impact of beta-lactam antibiotics on specific drugs which produce their pharmacological effects by increasing glutamatergic transmission is unknown. One such drug is morphine, which causes hyperthermia in rats, mediated by an increase in glutamatergic transmission. Since drugs (e.g. antibiotics) that enhance glutamate uptake also decrease glutamatergic transmission, we tested the hypothesis that ceftriaxone, a beta-lactam antibiotic, would block the glutamate-dependent portion of morphine-evoked hyperthermia.A body temperature assay was used to determine if ceftriaxone decreased morphine-induced hyperthermia in rats by increasing glutamate uptake.Body temperatures of rats treated with ceftriaxone (200 mg kg(-1), i.p. x 7 days) did not differ from rats receiving saline. Morphine (1, 4, 8 and 15 mg kg(-1), s.c.) caused significant hyperthermia. Pre-treatment with ceftriaxone, as described above, decreased the hyperthermic response to these doses of morphine. The effects of ceftriaxone were prevented by TBOA (0.2 micromol, i.c.v.), an inhibitor of glutamate transport.Ceftriaxone attenuated the hyperthermia caused by morphine, an effect prevented by inhibiting glutamate transport. Thus this effect of ceftriaxone was most likely mediated by increased glutamate uptake. These data revealed a functional interaction between ceftriaxone and morphine and indicated that a beta-lactam antibiotic decreased the efficacy of morphine in conscious rats.

SUBMITTER: Rawls SM

PROVIDER: S-EPMC2042926 | biostudies-other | 2007 Aug

REPOSITORIES: biostudies-other

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Project description:The goal of this work was to study the phenotypic susceptibility and resistance determinants of N. gonorrhoeae isolates to beta-lactam antimicrobials (benzylpenicillin and ceftriaxone). A total of 522 clinical isolates collected in Russia in 2015-2017 were analysed for susceptibility using the agar dilution method. DNA loci involved in antimicrobial resistance were identified using DNA microarray analysis and sequencing. Resistance to benzylpenicillin remained high, with 7.7% of isolates resistant (MICpen > 1 mg/L) and 47.5% of isolates showing intermediate susceptibility (MICpen = 0.12-1 mg/L). The most frequent resistance determinant (72.4% isolates) was the Asp345 insertion in penA, both as a single mutation and in combination with other mutations, particularly with the substitution Leu421Pro in ponA (39.0%). Mutations affecting the influx and efflux of drugs were also found, including amino acid substitutions in PorB (26.8% isolates) and delA in the promoter region of mtrR (22.8%). The accumulation of mutations in chromosomal genes (penA, pon, porA, and mtrR) led to a stepwise increase in MICpen to values characteristic of intermediate resistance. The presence of blaTEM plasmids was found in 25 isolates (4.8%), resulting in a strong increase in resistance to penicillin (MICpen > 16 mg/L) compared with the chromosomal mutations; 23 plasmids were of the African type with TEM-1 beta-lactamase, and two plasmids were of the Toronto/Rio type with TEM-135 beta-lactamase. Only three isolates were found with reduced susceptibility to ceftriaxone, with MICcef = 0.12-0.25 mg/L. Sequencing of penA did not reveal mutations associated with resistance to third-generation cephalosporins, and the gene structure was non-mosaic. The majority of isolates (21 of 25) carrying the blaTEM plasmid also contained the conjugative plasmid with tetM (resistance to tetracyclines), consistent with previously reported data that the presence of the conjugative plasmid facilitates the transfer of other plasmids associated with antimicrobial resistance.

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The beta-lactam antibiotic, ceftriaxone, attenuates morphine-evoked hyperthermia in rats.

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