Mousavi Zahra, Shafaghi Bijan, Kobarfard Farzad, Jorjani Masoumeh
Department of Toxicology, School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2007 Jan 12;554(2-3):145-9. doi: 10.1016/j.ejphar.2006.10.010. Epub 2006 Oct 17.
Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P<0.001). Sex differences in tolerance to morphine disappeared with gonadectomy of animals. There was also a significant sex difference in the glutamate level in the nucleus accumbens of morphine tolerant rats (P<0.001), ovariectomy of female rats decreased the glutamate level significantly (P<0.001), while gonadectomy did not change the glutamate level in males significantly. In conclusion, these experiments demonstrate that the excitatory amino acid release in the nucleus accumbens may be modulated by an estrogen-sensitive mechanism and play a role in the morphine analgesia and tolerance.
在对吗啡等阿片类药物的抗伤害感受作用产生耐受性的过程中观察到了性别差异，但确切的潜在机制仍不清楚。有证据表明性腺激素与包括阿片能和谷氨酸能系统在内的神经调节系统之间存在相互作用。我们使用体内微透析技术研究了吗啡耐受大鼠伏隔核中谷氨酸水平的性别差异以及性腺激素的作用。将微透析探针植入大鼠左侧伏隔核核心，收集脑脊液（CSF）透析液。通过带有荧光检测器的高效液相色谱法测量谷氨酸的浓度。结果表明，长期给予吗啡后，雄性大鼠对吗啡抗伤害感受作用的耐受性显著更高（P<0.001）。动物去势后，对吗啡耐受性的性别差异消失。吗啡耐受大鼠伏隔核中的谷氨酸水平也存在显著的性别差异（P<0.001），雌性大鼠卵巢切除后谷氨酸水平显著降低（P<0.001），而去势对雄性大鼠的谷氨酸水平没有显著影响。总之，这些实验表明伏隔核中兴奋性氨基酸的释放可能受雌激素敏感机制调节，并在吗啡镇痛和耐受性中发挥作用。
