Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.
Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.
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大麻素CB2受体的选择性激活抑制了用化学治疗剂紫杉醇在大鼠中诱导的神经性伤害受伤。
DOI：
10.1124/jpet.108.141994
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Hohmann AG
中科院分区：
文献类型：
--
作者：
Rahn EJ;Zvonok AM;Thakur GA;Khanolkar AD;Makriyannis A;Hohmann AG
大麻素CB2受体的激活抑制创伤性神经损伤引起的神经病理性疼痛。本研究旨在评价激活大麻素CB2受体对抗肿瘤药物紫杉醇化疗所致疼痛周围神经病的抑制作用。大鼠腹腔注射紫杉醇(2 mg/kg)。每天)，隔天四次，以诱导机械过敏(机械性痛觉过敏)。机械性痛觉超敏定义为用电子von Frey刺激器刺激足底后掌表面而使足爪退缩阈值降低。在接受紫杉醇治疗的动物中，相对于同时接受防晒霜：乙醇：生理盐水载体的组，发生了机械性痛觉异常。两种结构不同的大麻类CB2激动剂--氨基烷基吲哚(R，S)-AM1241(R，S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone)和大麻内酯AM1714(1，9-dihydroxy-3-(1′，1′-dimethylheptyl)-6H-benzo[c]chromene-6-one)—produced)可剂量相关地抑制全身给药后紫杉醇引起的机械性痛觉异常。预先给予CB2拮抗剂SR144528(5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1，3，3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide)，而不阻断CB1拮抗剂SR141716(5-(4-chlorophenyl)-1-(2，4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)，可阻断(R，S)-AM1241和AM1714的抗痛觉异常作用。此外，(R)-AM1241，而不是(S)-AM1241，相对于载体治疗或注射前阈值，抑制了紫杉醇诱发的机械性超敏反应，与CB2的调节一致。单独给予CB1或CB2拮抗剂均不能改变紫杉醇引起的机械性痛觉异常。此外，(R，S)-AM1241没有改变接受乳油载体替代紫杉醇的大鼠的爪子收缩阈值，而AM1714产生了适度的抗伤害效应。我们的数据表明，大麻素CB2受体可能是治疗化疗所致神经病的重要靶点。
Activation of cannabinoid CB2 receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB2 receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the anti-tumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p. per day) on four alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the cremophor: ethanol: saline vehicle at the same times. Two structurally distinct cannabinoid CB2 agonists—the aminoalkylindole (R,S)-AM1241 ((R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone) and the cannabilactone AM1714 (1,9-dihydroxy-3-(1′,1′-dimethylheptyl)-6H-benzo[c]chromene-6-one)—produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia following systemic administration. Pretreatment with the CB2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide), but not the CB1 antagonist SR141716 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide), blocked the anti-allodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or pre-injection thresholds, consistent with mediation by CB2. Administration of either the CB1 or CB2 antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the cremophor vehicle in lieu of paclitaxel whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB2 receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy.
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影响因子：
3.3
作者：
Nackley, AG;Makriyannis, A;Hohmann, AG
通讯作者：
Hohmann, AG
影响因子：
7.3
作者：
Bingham, B.;Jones, P. G.;Kennedy, J. D.
通讯作者：
Kennedy, J. D.
影响因子：
3.4
作者：
Hohmann, AG
通讯作者：
Hohmann, AG
影响因子：
2.5
作者：
LEE, YW;CHAPLAN, SR;YAKSH, TL
通讯作者：
YAKSH, TL
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M