The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects
The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects
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DOI：
10.1016/j.neuropharm.2010.09.004
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发表时间：
2011-02-01
影响因子：
4.7
通讯作者：
Lichtman, Aron H.
中科院分区：
文献类型：
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作者：
Kinsey, Steven G.;Mahadevan, Anu;Lichtman, Aron H.
虽然Delta(9)-四氢大麻酚(THC)和其他CB1/CB2混合受体激动剂已被证实具有抗伤害效应，但它们的拟心性作用和滥用的可能性抑制了人们对其治疗开发的热情。相反，CB2受体选择性激动剂已被证明可以减轻疼痛和炎症，而不会引起明显的大麻素行为影响。在本研究中，我们开发了一种新型的乙基磺酰胺THC类似物，0-3223，并在一组临床前疼痛模型中比较了它与强大的CB1/CB2受体激动剂CP55,940的药理作用。竞争性大麻素受体结合实验表明，0-3223对CB2的选择性大约是CBI受体的80倍。此外，0-3223在[S-35]GTP-γS结合中表现为完整的Cb2受体激动剂。0-3223可减少福尔马林实验各时相的伤害性行为，减少坐骨神经慢性缩窄性损伤(CCI)模型的热痛敏反应，减轻足底注射内毒素所致的水肿和热痛敏反应。这些作用可被CB2受体选择性拮抗剂SR144528预先阻断，但不能被CB1受体拮抗剂利莫那班阻断。与CP55940不同，0-3223在热板试验、体温过低或运动障碍中没有引起急性抗伤害效应，如在旋转棒试验中评估的那样。这些数据表明，CB2受体选择性激动剂0-3223可以减少炎症和神经病理性伤害性感受，而不影响基本的伤害性感受或引发明显的行为效应。此外，这种化合物可以作为模板来开发新的CB2受体激动剂，具有更高的受体选择性和更强的治疗炎症性和神经病理性疼痛的效力。(C)2010爱思唯尔有限公司。保留所有权利。
Although Delta(9)-tetrahydrocannabinol (THC) and other mixed CB1/CB2 receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB2 receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, 0-3223, and compared its pharmacological effects to those of the potent, mixed CB1/CB2 receptor agonist, CP55,940, in a battery of preclinical pain models. Competitive cannabinoid receptor binding experiments revealed that 0-3223 was approximately 80-fold more selective for CB2 than CBI receptors. Additionally, 0-3223 behaved as a full CB2 receptor agonist in [S-35]GTP gamma S binding. 0-3223 reduced nociceptive behavior in both phases of the formalin test, reduced thermal hyperalgesia in the chronic constriction injury of the sciatic nerve (CCI) model, and reduced edema and thermal hyperalgesia elicited by intraplantar injection of LPS. These effects were blocked by pretreatment with the CB2 receptor-selective antagonist SR144528, but not by the CB1 receptor antagonist, rimonabant. Unlike CP55,940, 0-3223 did not elicit acute antinociceptive effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test. These data indicate that the CB2 receptor-selective agonist, 0-3223, reduces inflammatory and neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects. Moreover, this compound can serve as a template to develop new CB2 receptor agonists with increased receptor selectivity and increased potency in treating inflammatory and neuropathic pain. (C) 2010 Elsevier Ltd. All rights reserved.