Minocycline potentiates the anti-hyperalgesic effect of ceftriaxone in CCI-induced neuropathic pain in rats

Abstract

Glutamate neurotoxicity and pro-inflammatory cytokines have an important role in the central sensitization of neuropathic pain. The purpose of the present study was to evaluate anti-hyperalgesic effect of repeated administration of ceftriaxone, which selectively activates and increases the expression of glutamate transporter, as well as minocycline, a selective inhibitor of microglia activation, either alone or together in Wistar rats subjected to the chronic constriction injury (CCI) of sciatic nerve. Ceftriaxone (100, 150 and 200 mg/kg) and minocycline (25, 50 and 100 mg/kg) were administered intraperitoneally from the day of surgery for seven consecutive days. Thermal hyperalgesia was assessed by focal radiant heat source on the hind paw of animals one day before surgery and on 3, 5, 7, 10 and 14 days following that. Ceftriaxone dose dependently, attenuated thermal hyperalgesia in animals. None of the administered doses of minocycline affected the CCI induced-thermal hyperalgesia in neuropathic animals. A fixed dose of minocycline (50 mg/kg) combined with three different doses of ceftriaxone administered for 7 consecutive days yielded a potentiating effect in the enhancing latency time to noxious thermal stimulus remaining until the 14th day post-surgery. The results suggest that modulation of microglia activity could have a supportive role in the improvement of CCI-induced thermal hyperalgesia and combination of such classes of drugs which have no antibiotic effects could be a new and promising therapeutic strategy for treatment.

Keywords: Ceftriaxone; Minocycline; Neuropathic pain; Rat; Thermal hyperalgesia.

Fig. 1

Time course of the antihyperalgesic effects produced by repeated administration of minocycline (Min 25, 50 and 100 mg/kg, A) and ceftriaxone (Cef 100,150, and 200 mg/kg, B), as well as the combination of a fixed dose of minocycline (50 mg/kg) with three different doses of ceftriaxone (100,150, and 200 mg/kg) in chronic constriction injury (CCI)animals (C, D and E, respectively). Administration of drugs was performed once daily from the day of surgery, for 7 consecutive days. Dotted horizontal bars indicate the duration of drug administration. Withdrawal threshold to radiant heat stimulus was assessed at days 3, 5,7,10, and 14 post-surgery. Data were analyzed by two-way analysis of variance (ANOVA) followed by Bonferroni's post-hoc analysis to examine the time-courses of behavioral changes after various treatments. Data were expressed as mean ± SEM for n=6-8/group. ^*P<0.05, ^**P<0.01 indicate significant difference in comparison to control (CCI-vehicle) group. Gabapentin (Gbp 100 mg/kg) is the reference drug.

Fig. 2

Antihyperalgesia effect produced by repeated i.p. co-administration of minocycline (Min 50 mg/kg) with A; ceftriaxone 100 mg/kg (Cef 100), B; ceftriaxone 150 mg/kg (Cef 150) and C; ceftriaxone 200 mg/kg (Cef 200) daily to animals subjected to chronic constriction injury(CCI) surgery. Data are expressed as the percentage of maximal possible effect (%MPE). Withdrawal threshold was assessed at days 3, 5, 7, 10, and 14 after surgery. Data were analyzed by one-way analysis of variance (ANOVA) followed by Tukey post-hoc test. Statistical significance between two groups (the theoretical response and the experimentally derived values) was evaluated using the Student's t-test and expressed as mean ± SEM for n=6-8 group.^*P<0.05, ^**P<0.01 comparison is made between observed and expected effects of drug combination with paired t test, #P<0.05, ##P<0.01, ###P<0.001 indicate significant change in comparison to control (CCI-vehicle) group.