Shu Haihua, Hayashida Masakazu, Huang Wenqi, An Ke, Chiba Shunsuke, Hanaoka Kazuo, Arita Hideko
Department of Anesthesiology, First Affiliated Hospital of Sun Yat-Sen University, 58# Zhongshan 2nd Road, Guangzhou, 510080, PR China.
J Ethnopharmacol. 2008 Apr 17;117(1):158-65. doi: 10.1016/j.jep.2008.01.029. Epub 2008 Feb 6.
In the previous studies, we demonstrated that an oriental herbal medicine, processed Aconiti tuber (PAT), at subanalgesic doses could inhibit or reverse the antinociceptive tolerance to morphine. In the present study, we compared the effect of PAT, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidin)cyclohexyl)-benzeneacetamide methane sulfonate hydrate (U50488H), a selective kappa opioid receptor (KOR) agonist, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, on the antinociceptive tolerance to morphine in the same experimental condition. Mice received subcutaneous morphine (10 mg/kg), and oral PAT at a subanalgesic dose (0.3 g/kg for mechanical or 1.0 g/kg for thermal test), or intraperitoneal U50488H at a subanalgesic dose (3 mg/kg), or MK-801 at a subanalgesic dose (0.1 mg/kg) once daily for 14 days. The mechanical nociceptive threshold was measured before, and at 60 min by tail pressure testing, and thermal nociceptive latency was measured before, and at 30 min by hot plate testing, after daily morphine injections. PAT and U50488H could not only inhibit the development of morphine tolerance but also reverse the already-developed morphine tolerance, while MK-801 could only inhibit the development of morphine tolerance but not reverse the already-developed morphine tolerance, in both mechanical and thermal nociceptive tests. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance, and that PAT may be superior to some NMDA receptor antagonists which do not reverse already-developed morphine tolerance.
在先前的研究中，我们证明了一种东方草药——炮制乌头（PAT），在亚镇痛剂量下可以抑制或逆转对吗啡的抗伤害感受性耐受。在本研究中，我们在相同实验条件下比较了PAT、反式-(+/-)-3,4-二氯-N-甲基-N-(2-(1-吡咯烷基)环己基)-苯乙酰胺甲磺酸盐一水合物（U50488H）（一种选择性κ阿片受体（KOR）激动剂）和(-)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐（MK-801）（一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂）对吗啡抗伤害感受性耐受的影响。小鼠皮下注射吗啡（10 mg/kg），并每天口服一次亚镇痛剂量的PAT（机械测试为0.3 g/kg，热测试为1.0 g/kg），或腹腔注射亚镇痛剂量的U50488H（3 mg/kg），或亚镇痛剂量的MK-801（0.1 mg/kg），持续14天。在每天注射吗啡后，通过尾压试验在给药前和给药后60分钟测量机械性伤害感受阈值，通过热板试验在给药前和给药后30分钟测量热伤害感受潜伏期。在机械性和热伤害感受测试中，PAT和U50488H不仅可以抑制吗啡耐受的形成，还可以逆转已形成的吗啡耐受，而MK-801只能抑制吗啡耐受的形成，不能逆转已形成的吗啡耐受。这些数据表明，PAT作为一种间接作用的KOR激动剂，与KOR激动剂在吗啡耐受方面具有共同的药理学特性，并且PAT可能优于一些不能逆转已形成的吗啡耐受的NMDA受体拮抗剂。
