急性乙醇中毒大鼠下丘脑阿片肽含量的变化及葛根素的干预研究

目的观察急性乙醇中毒大鼠下丘脑β-内啡肽（β—endorphine,β—EP）、亮脑啡肽（leu—enkephalin,LENK）和强啡肽A（dynorphin A,DynA）含量变化及葛根素的干预作用。方法选雄性Wistar大鼠30只,随机分为对照组、模型组和葛根素组,分别测定血中乙醇浓度变化,下丘脑β—EP,LENK,Dyn A的含量。结果葛根素组的血乙醇浓度比模型组低,与对照组相比,模型组大鼠下丘脑β-EP,LENK水平显著增高,DynA的含量变化不明显。葛根素组与模型组相比,β-EP,LENK水平均显著降低,Dyn A含量变化不明显。结论急性乙醇中毒时阿片肽释放增加,葛根素可能通过降低血乙醇浓度来抑制阿片肽的释放,对乙醇中毒起到治疗作用。     

Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum

The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.     

Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and κ-opioid receptor implicated

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5–140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by κ-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1–17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 μg/20 μl), a κ-opioid receptor antagonist, or dynorphin A (1–13) antibodies (25 μg/20 μl) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with κ-opioid receptor at spinal level.     

强啡肽对脊髓反射抑制作用的受体机制研究

目的 研究鞘内注射强啡肽（Dyn)A(1-13)对脊髓反射抑制作用的受体机制。方法 通过大鼠蛛网膜下腔置管后鞘内注射30nmol DynA(1-13)导致热辐射刺激甩尾反射消失的模型,检测在应用Dyn(A1-13)之前之后鞘内分别注射5、30、150nmol MK-801(NMDA)受体非竞争性拮抗剂）对甩尾反射消失的影响。结果 MK－801在预先给药时对DynA(1-13）所致大鼠甩尾反射消失有剂量相关的保护作用,其中150nmolMK-801的保护率达90％。在迟后给药时则会产生时间相关的保护作用,30、150nmolMK－801的作用峰值分别在15、30min。结论 Dyn致大鼠甩尾反射消失作用至少部分是由NMDA受体介导的。     

强啡肽和兴奋性氨基酸在脊髓损伤中的作用

目的：探讨神经毒素兴奋性氨基酸（ Ｅ Ａ Ａ）和神经肽在脊髓损伤中的作用。方法：应用高效液相色谱法检测脊髓损伤后伤段组织中谷氨酸（ Ｇｌｕ）、天门冬氨酸（ Ａｓｐ）两种 Ｅ Ａ Ａ 的含量变化;应用放射免疫分析技术测定脊髓损伤伤段组织中神经肽之一强啡肽 Ｄｙｎ Ａ１～１３ 含量的变化;观察了蛛网膜下腔注射 Ｇｌｕ、 Ｄｙｎ Ａ１～１３、兴奋性氨基酸受体拮抗剂３－ （２－ 羧基哌嗪）丙基－ １－ 磷酸（ Ｃ Ｐ Ｐ）、 Ｄｙｎ Ａ１～１３抗血清（ Ａｎ－ Ｄｙｎ Ａ１～１３）对大鼠脊髓损伤的影响。结果： Ｅ Ａ Ａ 和 Ｄｙｎ Ａ１～１３均随损伤程度的加重进行性升高,且呈时间依赖性变化。外源性 Ｇｌｕ 可显著加重脊髓损伤的严重程度, Ｄｙｎ Ａ１～１３ 可产生剂量相关的后肢瘫痪。而 Ｃ Ｐ Ｐ和 Ａｎ－ Ｄｙｎ Ａ１～１３对大鼠脊髓继发性损伤有保护作用。结论：实验结果提示 Ｅ Ａ Ａ、 Ｄｙｎ Ａ１～１３作为神经毒素参与脊髓损伤后的继发性损伤过程。