[Decrease in glutamate level in cerebral cortex and lumbar region of spinal cord of rat: a potential mechanism for minocycline in attenuating morphine-induced tolerance]

Chronic opiate administration induces tolerance to the analgesic effect. Despite extensive investigations in this ground, the precise cellular mechanisms underlying opioid tolerance and dependence remain controversial. Several studies have indicated that glutamatergic transmission and nitric oxide/ Nmethyl D-aspartate [NMDA] pathway could play an important role in morphineinduced tolerance. The main aim of this study was to evaluate the effects of intracerebro- ventricular [ICV] administration of minocycline [a second-generation tetracycline] on morphine-induced tolerance and elevation of glutamate level in cerebral cortex and lumbar region of spinal cord of rats after administration of morphine. Different groups of rats received either morphine [IP] and distilled water [ICV] or morphine [IP] and different doses of minocycline [ICV] or minocycline alone once per day. Nociception was assessed using a hot plate apparatus. The glutamate concentration in both regions was measured with a high performance liquid chromatography [HPLC] apparatus. The results indicated that ICV administration of minocycline with doses of 60, 120, 240 micro g/10micro l/rat attenuated the morphine-induced tolerance and decreased glutamate level in the cerebral cortex. But glutamate level in the lumbar spinal cord decreased after administration of minocycline with doses of 120, 240 micro g/10micro l/rat. We found that central administration of minocycline attenuated morphine-induced increase of glutamate level in the cortex and lumbar spinal cord of rats which can be regarded as a possible mechanism for effect of minocycline on morphine-induced tolerance

[Evaluation of the effect of intra cerebroventricular administration of CCPA on reduction of tolerance to the analgesic effect of morphine in rat]

Continuous or long term use of opiate drugs may cause tolerance to the analgesic effect of these drugs, which limits the therapeutic efficacy of these drugs. In this study we evaluated the effects of central administration of 2-chloro-N6-cyclopentyladenosine [CCPA], a selective A1 receptor agonist, on morphine-induced tolerance in rats. Different groups of rats received daily intracerebroventricular [ICV] morphine [10 mg/kg, ip] in combination with saline 5 micro l/rat, or intracerebroventricular [icv] CCPA [20, 40, 80 micro g/5 micro l/rat]. Nociception was assessed by use of a hotplate apparatus [55 +/- 0.5°C]. Using a hot-plate device, the pain inducing effect was recorded when the rat licked its hind paw or jumped. Results showed that different doses of CCPA [20, 40, 80 micro g/5 micro l/rat, icv] delayed the tolerance to the analgesic effect of morphine for 4, 8, and 10 days respectively. In addition, our results showed that CCPA increased the total analgesic effect of morphine. We found that intracerebroventricular administration of CCPA, A1 selective agonists, prevented morphine-induced tolerance to the analgesic effect in rat