The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB₂ receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy.
The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB₂ receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy.
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DOI：
10.1186/1744-8069-8-71
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发表时间：
2012-09-22
期刊：
影响因子：
3.3
通讯作者：
Hohmann AG
中科院分区：
文献类型：
--
作者：
Deng L;Guindon J;Vemuri VK;Thakur GA;White FA;Makriyannis A;Hohmann AG
化疗药物通过仍鲜为人知的机制产生剂量限制性的周围神经病变。我们以前证明了AM1710，一种大麻内酯CB2激动剂，产生抗伤害作用而不产生中枢神经系统(CNS)相关的副作用。本研究旨在观察AM1710对不同化疗药物(顺铂和紫杉醇)诱发的神经病理性疼痛的抗伤害性作用。第二个目标是研究α-趋化因子受体(CXCR4)信号对化疗引起的神经病变和CB2激动剂疗效的潜在贡献。AM1710(0.1、1或5 mg/kg I.P.)抑制顺铂和紫杉醇模型中机械性和冷性痛觉异常的维持。CB2拮抗剂AM630(3 mg/kg i.p.)可阻断AM1710的抗痛觉异常反应，而CB1拮抗剂AM251(3 mg/kg i.p.)不能阻断AM1710的拮抗作用，这与CB2介导的作用一致。相反，用其受体拮抗剂AMD3100(10 mg/kg i.p.)阻断CXCR4信号传导。不能减弱顺铂或紫杉醇诱导的机械或冷过敏。此外，阻断CXCR4信号未能改变AM1710在紫杉醇模型中的抗痛觉过敏作用，进一步表明了不同的作用机制。我们的结果表明，AM1710激活大麻素CB2受体可以抑制两种不同的化疗诱导的神经病理性疼痛模型中的机械性和冷敏性痛觉异常。相比之下，CXCR4信号并不有助于维持化疗引起的已建立的神经病变或AM1710的疗效。我们的研究表明，CB2受体是治疗由顺铂和紫杉醇化疗药物引起的中毒性神经病变的一个有前途的治疗靶点。
Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy. AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action. Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.
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影响因子：
3.3
作者：
Bhangoo SK;Ripsch MS;Buchanan DJ;Miller RJ;White FA
通讯作者：
White FA
影响因子：
3.7
作者：
Carozzi, Valentina A.;Chiorazzi, Alessia;Cavaletti, Guido
通讯作者：
Cavaletti, Guido
影响因子：
7.3
作者：
Benamar, Khalid;Yondorf, Menachem;Adler, Martin W.
通讯作者：
Adler, Martin W.
DOI：
10.1124/jpet.107.135053
发表时间：
2008-05-01
影响因子：
3.5
作者：
Benamar, Khalid;Geller, Ellen B.;Adler, Martin W.
通讯作者：
Adler, Martin W.
影响因子：
5.3
作者：
Authier, N;Gillet, JP;Coudore, F
通讯作者：
Coudore, F