慢性神经痛大鼠鞘内联合应用吗啡和氯胺酮在脊髓上水平的抗伤害性作用及对吗啡耐受的影响

目的研究鞘内联合应用吗啡和氯胺酮对慢性神经痛大鼠的抗伤害作用机制及对吗啡耐受的影响。方法 40只Wistar大鼠,体质量220～260 g,制备坐骨神经结扎模型并进行鞘内置管,随机分为5组(n=8):B组为空白对照组;C组鞘内注射0.9%盐水10μL;K组鞘内注射氯胺酮50μg;M组鞘内注射吗啡20μg;KM组鞘内注射吗啡10μg和氯胺酮25μg。坐骨神经结扎术后第4天开始鞘内给药,每日1次,连续7 d。用药7d后处死大鼠,取大脑皮质、海马、脑干组织,硝酸还原酶法测定NO浓度和NOS活性。结果与B组比较,C和K组脑干NO浓度升高,M组皮质、海马、脑干中NO浓度均升高;与C组比较,M组皮质、海马NO浓度升高,KM组海马、脑干中NO浓度降低;与M组比较,KM组皮质、海马、脑干NO浓度均降低(P<0.05或0.01)。与B组比较,C、K和M组皮质、海马、脑干中NOS活性均升高;与C和M组比较,KM组皮质、海马、脑干中NOS活性均降低(P<0.05或0.01)。结论神经病理性痛大鼠鞘内联合应用吗啡和氯胺酮可在脊髓上水平产生抗伤害性作用,并可抑制吗啡耐受的形成,这可能与大脑皮质、海马、脑干的NO水平和NOS活性有关。

Effects of intrathecal coadministration morphine and ketamine on antinociception on supraspinal level and morphine tolerance in rats with chronic neuropathic pain

Objective To investigate the antinociceptive mechanism on supraspinal level of intrathecally coadministered morphine and ketamine and the effects on morphine tolerance in rats with chronic neuropathic pain.Methods Forty Wistar rats weighing 220~260 g were prepared with loosely constrictive ligatured around sciatic nerve and intrathecal catheters were inserted.The rats were randomly allocated into five groups with 8 animals in each group:Group C(saline 10 μL);Group M(morphine 20 μg);Group K(ketamine 50 μg);Group KM(morphine 10 μg and ketamine 25 μg);Group B(no drug or operation was available).Drugs were administrated on the 4th day after chronic constriction injury(CCI)of the sciatic nerve,once a day for 7 days.7 days later,the rats were decapitated and cerebral cortex,hippocampus and brainstem were immediately dissected on ice.NOS activity and NO content were measured by spectrophotometry.Results Compared with group B,the production of NO in group C and K were higher at brainstem,it was also higher in group M at cerebral cortex,hippocampus and brainstem;Compared with group C,the content of NO in group M was higher at cerebral cortex and hippocampus,however,it was lower in group KM at hippocampus and brainstem;Compared with group M,NO in group KM was lower at cerebral cortex,hippocampus and brainstem(P<0.05 or 0.01).Compared with group B,the activities of NOS in group C,K and M were higher;Compared with group C and M,NOS activity in group KM was lower at cerebral cortex,hippocampus and brainstem(P<0.05 or 0.01).Conclusion Morphine plus ketamine administered intrathecally can prevent tolerance to morphine and has antinociception on supraspinal level,these may related to the level of NO and activity of NOS in cerebral cortex,hippocampus and brainstem.