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چکیده
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Introduction: Morphine has unfavorable side effects including analgesic tolerance. However, the precise underlying mechanism of morphine tolerance have remained elusive. Different brain regions including the striatum and cerebellar cortex are affected by morphine. A growing body of evidence shows that calcium channels are involved in morphine tolerance. For example, it has been shown that blockade of L-type calcium channels could abolish the development of opioid-induced analgesic tolerance. The aim of this study was to examine changes in the gene expression of different voltage-gated calcium channels, including Cav1.1, Cav1.2, Cav2.2, and Cav3.1 in the striatum and cerebellar cortex after induction of morphine tolerance in rats. Method: Male Wistar rats were used in which morphine tolerance was induced with 10 days injections of morphine 10 mg/kg (S.C.) twice per day. A control group received saline (1 ml/kg) twice daily for 10 consecutive days. On day 10, morphine-induced analgesic tolerance was assessed using a hotplate test of analgesia. For gene expression study, each rat was sacrificed, the whole brain was removed, and the striatum and cerebellar cortex were dissected in both groups on day 10 of the schedule. The gene expression was examined using a quantitative RT-PCR method. The hotplate data was analyzed with a mixed two-way ANOVA. The real time-PCR data was analyzed using the 2-ΔΔCT method and an independent t-test was used for pairwise comparisons. P<0.05 was set as a statistically significant level. Result: The results showed that the morphine treatments induced analgesic tolerance on day 10 of the treatments compared to control group (P<0.001). The results of the RT-PCR indicated significant increases in Cav1.2 and Cav3.1 mRNA levels (P<0.001), but significant decreases in the gene expression of Cav1.1 (P<0.001) and Cav2.2 (P<0.05) in the cerebellar cortex of morphine-tolerant rats compared with the saline-treated control group. The results also indicated significant increase in Cav3.1 mRNA level (P<0.01), but significant decrease in the gene expression of Cav1.1 (P<0.001) in the striatum. No significant changes were detected in expression of Cav1.2 and Cav2.2 in the striatum between the experimental groups. Conclusion: It can be concluded that repeated morphine treatments affect expression of voltage-dependent calcium channels in the cerebellar cortex and striatum. We propose that changes in voltage-dependent calcium channels may underlie, at least partly, morphine-induced analgesic tolerance.
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