title: Beta-lactam antibiotic reduces morphine analgesic tolerance in rats through GLT-1 transporter activation.
abstract: Glutamate transporter subtype 1 (GLT-1) activation is a promising - and understudied - approach for managing aspects of morphine tolerance caused by increased glutamatergic transmission. Identification of beta-lactam antibiotics as pharmaceuticals which activate GLT-1 transporters prompted us to hypothesize that repeated beta-lactam antibiotic (ceftriaxone) administration blocks development of tolerance to morphine antinociception through GLT-1 activation. Here, we injected rats with morphine (10mg/kg, s.c.) twice daily for 7 days to induce tolerance and used the hot-plate assay to determine antinociception on days 1, 4 and 7 of repeated morphine administration. Ceftriaxone and a selective GLT-1 transporter inhibitor dihydrokainate (DHK) were co-administered with morphine to determine if GLT-1 activation mediated the ceftriaxone effect. Tolerance was present on days 4 and 7 of repeated morphine administration. Ceftriaxone (50, 100 or 200mg/kg, i.p.) administration dose-dependently blocked development of morphine tolerance. DHK (10mg/kg, s.c.), administered 15 min before each morphine injection, prevented inhibition of morphine tolerance by ceftriaxone (200mg/kg, i.p.). These results identify an interaction between ceftriaxone and morphine in opioid-tolerant rats and suggest beta-lactam antibiotics preserve analgesic efficacy during chronic morphine exposure.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University Health Sciences Center, 3307 North Broad Street, Philadelphia, PA 19140, USA. scott.rawls@temple.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
authors.forename: Michael
authors.initials: M
authors.lastname: Zielinski
authors.forename: Hiren
authors.initials: H
authors.lastname: Patel
authors.forename: Steven
authors.initials: S
authors.lastname: Sacavage
authors.forename: David A
authors.initials: DA
authors.lastname: Baron
authors.forename: Digvesh
authors.initials: D
authors.lastname: Patel
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002443:Ceftriaxone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000819:agonists* / Q000037:antagonists & inhibitors; D006358:Hot Temperature; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; C020889:dihydrokainic acid; D002443:Ceftriaxone; D009020:Morphine; D007608:Kainic Acid