minocycline and Morphine-Dependence

Accumulating evidence indicated that minocycline, a glial cell modulator, is able to modify a variety of morphine effects. Here, we investigated minocycline effects on electrical activity of nucleus accumbens (NAc) neurons using single unit recording in urethane-anesthetized rats. In addition, we investigated whether minocycline can modify the effects of morphine on NAc neural activity during reinstatement of morphine-seeking behavior. Minocycline increased the NAc firing activity in intact animals. Electrophysiological recording in morphine-treated animals was performed, following the acquisition of morphine-induced conditioned place preference (5 mg/kg, s.c., 3 days) and a drug-free extinction period. In acutely minocycline- treated animals, the neurons were recorded for 40 minutes following a single injection of either minocycline (50 μg/5 μl, i.c.v.) or saline. Then a priming dose of morphine (1 mg/kg, s.c.) was injected while the recording was continued for an additional 40 minutes. Minocycline significantly increased the firing rates of neurons and significantly modified morphine inhibitory effects on NAc neurons. In subchronically minocycline-treated groups, the rats were given daily injections of minocycline (50 μg/5 μl, i.c.v) during the extinction period. Then, on the reinstatement day, NAc neurons were recorded for 10 minutes, the priming dose of morphine was administered and the recording was continued for 45 minutes. Our results showed the failure of minocycline to significantly modify the inhibitory effects of morphine. In conclusion, our findings indicated that minocycline modifies morphine-induced decreases in the firing rates of NAc neurons in the reinstatement phase.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Conditioning, Classical; Disease Models, Animal; Drug-Seeking Behavior; Electrodiagnosis; Male; Minocycline; Morphine; Morphine Dependence; Neurons; Nucleus Accumbens; Rats; Rats, Wistar

Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 μg/0.5 μL) or saline (0.5 μL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse.

Topics: Animals; Male; Minocycline; Morphine; Morphine Dependence; Neuroglia; Nucleus Accumbens; Rats; Rats, Wistar; Substance-Related Disorders

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.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Area Under Curve; Drug Tolerance; Glutamic Acid; Male; Minocycline; Morphine; Morphine Dependence; Neuroprotective Agents; Nitric Oxide; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Riluzole