Central Administration of Minocycline and Riluzole Prevents Morphine-Induced Tolerance in Rats

Long-term exposure to opiates induces tolerance to the analgesic effect. The neurobiological mechanism of this phenomenon is not completely clear. In this study, we evaluated the effects of central administration of minocycline (a tetracycline derivative) and riluzole (an antiglutamatergic drug) on morphine-induced tolerance in rats. Groups of rats received daily morphine (10 mg/kg, IP) in combination with saline (10 microL/rat, intracerebroventricular [ICV]) or 1% Tween 80 (10 microL/rat, ICV) or minocycline (60, 120, and 240 microg/10 microL per rat, ICV) or riluzole (20, 40, 80 microg/10 microL per rat, ICV). Nociception was assessed using hotplate apparatus (55 degrees C +/- 0.5 degrees C). Hotplate latency was recorded when the rat licked its hindpaw. Baseline latencies were determined once per day for each rat, then morphine (10 mg/kg) was injected. After 20 min, the above-mentioned drugs were administered and postdrug latency was measured 10 min after the injection of drugs or vehicles. Results showed that ICV administration of minocycline and riluzole delayed morphine-induced tolerance. Morphine tolerance was complete after 8 days in the control groups but was complete in the groups treated with minocycline (120 microg/10 microL per rat) and riluzole (80 microg/10 microL per rat) on the 13th day. In addition, our results showed that minocycline and riluzole increased the total analgesic effect of morphine (area under the curve of the percentage of maximal possible effect values). The effects of minocycline on nitric oxide and the glutamatergic system and the effect of riluzole on the glutamate system are potentially important mechanisms in delaying morphine-induced tolerance.