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 (10 mg/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 200 mg/kg, i.p.) administration dose-dependently blocked development of morphine tolerance. DHK (10 mg/kg, s.c.), administered 15 min before each morphine injection, prevented inhibition of morphine tolerance by ceftriaxone (200 mg/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.