归元片对小鼠吗啡耐受和痛觉过敏的抑制效应

摘要

目的评价归元片对吗啡镇痛以及吗啡所致耐受和痛觉过敏的影响。方法①吗啡急性耐受模型小鼠每隔1 h分别ig给予归元片200，400和800 mg·kg－1，15 min后sc给予吗啡10 mg·kg－1，连续给9 h，分别于24和48 h再给予吗啡10 mg·kg－1；②吗啡慢性耐受模型小鼠每日ig给予归元片200，400和800 mg·kg－1，15 min后sc给予吗啡10 mg·kg－1，连续给8 d，d 9单独sc给予吗啡10 mg·kg－1；③吗啡已形成耐受模型小鼠每日sc给予吗啡10 mg·kg－11次，连续给8 d，分别于d 1，d 4或d 7起联合给予归元片200 mg·kg－1，d 9再单独sc给予吗啡10 mg·kg－1。采用小鼠热板测定给药前痛阈值( T0)和给药后痛阈值( T1)，计算最大可能镇痛率(％MPAE)。采用分光光度法检测脊髓中一氧化氮合酶( NOS)活性和一氧化氮( NO )含量。结果热板实验中归元片镇痛效应的 ED50为523.5 mg·kg－1。归元片200和400 mg·kg－1能延长吗啡镇痛时间，并使吗啡镇痛ED50值从4.67 mg·kg－1分别降至3.14和0.65 mg·kg－1。在吗啡急性和慢性耐受模型中，归元片能抑制％MPAE值和给药前痛阈值的降低( P<0.05)；在已形成的耐受模型中，归元片能快速逆转已降低的％MPAE值( P<0.05)，且当该复方制剂于d 1起与吗啡联用时，能有效抑制吗啡所致脊髓中NOS活性和NO含量的升高( P<0.01)。结论归元片能有效增强吗啡镇痛，延长吗啡镇痛的持续时间，抑制吗啡所致耐受和痛觉过敏的发展，并可能具有神经保护作用。%OBJECTlVE To investigate the effect of Guiyuan tablets on the analgesic effect of morphine and morphine-induced tolerance and hyperalgesia. METHODS ① The model of morphine-induced acute tolerance Mice were ig treated with Guiyuan tablets 200, 400 and 800 mg·kg-1 and 15 min later were sc treated with morphine 10 mg·kg-1 every hour for consecutive 9 h. At 24 and 48 h, they were sc treated with morphine 10 mg·kg-1 alone, respectively.②The model of morphine-induced chronic tolerance Mice were ig treated with Guiyuan tablets 200, 400 and 800 mg·kg-1 and 15 min later were sc treated with morphine 10 mg·kg-1 every day for consecutive 8 d. On d 9, the mice were sc treated with morphine 10 mg·kg-1 alone. ③ The model of morphine-induced established tolerance. Mice were sc treated with morphine 10 mg·kg-1 every day for consecutive 8 d. On d 1, d 4 or d 7, the mice began to be ig co-administered with Guiyuan 200 mg·kg-1 . On d 9, they were sc treated with morphine 10 mg·kg-1 alone. The hot-plate test was used to detect the values of the baseline latency ( T0 ) and the post-treatment latency ( T1 ) before the percentage of maximal possible analgesic effect (%MPAE) was calculated. Spec-trophotometry was used to detect the nitric oxide synthase ( NOS) activity and the nitric oxide ( NO) con-tent in the tissue of the spinal cord. RESULTS The ED50 of the analgesic effect of Guiyuan tablets was 523.5 mg·kg-1 in the hot-plate test. Guiyuan tablets 200 and 400 mg·kg-1 prolonged the duration of mor-phine anti-nociception and deceased its ED50 from 4.67 to 3.14 and 0.65 mg·kg-1, respectively. ln the models of both acute and chronic tolerance, Guiyuan tablets prevented the decrease of the%MPAE and the baseline latencies ( P<0. 05 ) . ln the model of morphine-induced established tolerance, Guiyuan tablets rapidly reversed the decrease of%MPAE( P<0.05) , and this compound preparation which began to be co-administered with morphine from d 1 could significantly inhibit the increase of the NOS activity and NO content induced by morphine in the spinal cord ( P<0.01) . CONCLUSlON Guiyuan tablets are capable of enhancing the analgesic effect of morphine, prolonging the duration of morphine anti-nocicep-tion, preventing the development of morphine-induced tolerance and hyperalgesia, and might have neuroprotective effect.