Two-way ANOVA revealed a significant drug interaction ((4,26)=39.05, (4,104)=17.03, (8,104)=12.00, analysis confirmed our results with riluzole (Figure 4b). Open in a separate window Figure 4 Riluzole (RLZ), an inhibitor of glutamate release, attenuated morphine-evoked hyperthermia. by the Temple University Animal Care and Use Committee. Male SpragueCDawley rats (Zivic-Miller, Pittsburgh, PA, USA) weighing 200C250?g (age, 60C80 days) were housed two per cage for a minimum of 5 days before experimental use. Rats were maintained on a 12-h light/dark cycle and fed rat chow and water study (Cechova and Zuo, 2006). Following i.c.v. experiments, injection sites were verified with an injection of 0.1% Evan’s blue (5?analysis. In all cases, values of (6,36)=46.09, (4,124)=21.09, (10,124)=15.34, analysis confirmed the effects of TBOA (Figure 3b). Open in a separate window Figure 3 The glutamate uptake blocker, DL-threo-6,36=28.60, analysis. Glutamate release inhibitor attenuates morphine-evoked hyperthermia The effects of riluzole (2.5 and 5?mg?kg?1, i.p.) on the hyperthermia caused by a single dose of morphine (4?mg?kg?1, s.c.) are presented in Figure 4. Two-way ANOVA revealed a significant drug interaction ((4,26)=39.05, (4,104)=17.03, LY404187 (8,104)=12.00, analysis confirmed our results with riluzole (Figure 4b). Open in a separate window Figure 4 Riluzole (RLZ), an inhibitor of glutamate release, attenuated morphine-evoked hyperthermia. (a) Time course: rats were injected with riluzole (2.5 or 5?mg?kg?1, i.p.) or vehicle (VEH). Thirty minutes later, morphine (MOR) (4?mg?kg?1, s.c.) or VEH was injected. Data are expressed as the means.e.m. of the change in body temperature (analysis. Discussion The present study investigated the effect of ceftriaxone, a representative em /em -lactam antibiotic, on the hyperthermia caused by morphine. We hypothesized that repeated ceftriaxone administration would block morphine-induced hyperthermia. This is, in fact, what was found. Ceftriaxone blocked a significant proportion of the hyperthermia caused by morphine and these effects were prevented by a broad spectrum glutamate transport inhibitor (TBOA). The effects of ceftriaxone on morphine-induced hyperthermia were similar to the effects of a glutamate release inhibitor and a NMDA antagonist (Rawls em et al /em ., 2003), which both significantly inhibit the hyperthermic response to morphine. These data suggest that morphine-evoked hyperthermia is controlled by the endogenous glutamate system and can be inhibited by drugs that increase glutamate uptake ( em /em -lactam antibiotics), decrease glutamate release (riluzole) and block glutamatergic transmission at NMDA receptors (dextromethorphan) (Rawls em et al /em ., 2003). The attenuation of morphine-induced hyperthermia by riluzole supports our finding that NMDA receptor blockade reduces the hyperthermic response to morphine and extends the finding to include a role for glutamate release in the LY404187 hyperthermia caused by morphine (Rawls em et al /em Pdgfrb ., 2003). The major mechanism of action of riluzole is the inhibition of glutamate release from presynaptic terminals in the CNS (Malgouris em et al /em ., 1989; Martin em et al /em ., LY404187 1993; Prakriya and Mennerick, 2000). Riluzole affects a number of ion channels that regulate glutamate release, including voltage-activated calcium channels (Huang em et al /em ., 1997), voltage-dependent sodium channels (Stefani em et al /em ., 1997) LY404187 and potassium channels (Duprat em et al /em ., 2000). Riluzole also increases glutamate uptake in synaptosomal preparations and blocks some of the post-synaptic effects of glutamate by blocking NMDA receptors (Doble, 1996; Frizzo em et al /em ., 2004). Regardless of the exact mechanism, the outcome is that riluzole decreases glutamatergic transmission. The major finding of the present study is that ceftriaxone decreased a significant proportion of the hyperthermic response to morphine. The effect was observed after 7 days of repeated ceftriaxone administration, but not after a single, acute injection of ceftriaxone. These.