Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.
Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.
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DOI：
10.1016/j.pain.2011.03.038
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发表时间：
2011-09
期刊：
影响因子：
7.4
通讯作者：
Hohmann AG
中科院分区：
文献类型：
--
作者：
Gutierrez T;Crystal JD;Zvonok AM;Makriyannis A;Hohmann AG
使用药物自我给药方法来检验大鼠会使用大麻素 CB2 激动剂自我治疗以减轻神经性疼痛状态的假设。 CB2 激动剂 (R,S)-AM1241（而非媒介物）的自我治疗可减轻因神经损伤而产生的机械超敏反应。将大鼠从 (R,S)-AM1241 切换到媒介物自我给药也降低了灭绝范式中的杠杆反应。 (R,S)-AM1241 自我给药不会改变假手术或幼稚动物的缩爪阈值。主动杠杆反应的百分比在幼稚组中自我施用载体或(R,S)-AM1241中相似。 CB2 拮抗剂 SR144528 阻断 (R,S)-AM1241 自我治疗的抗异常疼痛作用以及神经病（但不是幼稚）大鼠中主动杠杆反应的百分比。神经病组和假手术组在固定比率 1 (FR1) 方案上表现出相似的 (R,S)-AM1241 反应杠杆百分比。然而，当强化时间增加（至 FR6）时，神经病动物比假手术动物更加努力地获得 (R,S)-AM1241。 (R,S)-AM1241 对 FR1、FR3 或 FR6 的自我治疗可减轻神经损伤引起的机械性异常性疼痛。 (R,S)-AM1241 (900 µg i.v.) 未能产生在施用混合 CB1/CB2 激动剂 WIN55,212-2 (0.5 mg/kg i.v.) 后观察到的运动共济失调。我们的结果表明，大麻素 CB2 激动剂可用于治疗神经性疼痛，且药物滥用可能性和中枢神经系统 (CNS) 副作用有限。这些研究验证了使用药物自我给药方法来识别滥用潜力有限的非精神药物镇痛药。这些方法提供了阐明新型镇痛药的潜力，这些镇痛药可以抑制自发性神经性疼痛，而传统的诱发疼痛评估无法测量这种疼痛。
Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB2 agonist to attenuate a neuropathic pain state. Self-medication of the CB2 agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB2 antagonist SR144528 blocked both anti-allodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3 or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900 µg i.v.) failed to produce motor ataxia observed following administration of the mixed CB1/CB2 agonist WIN55,212-2 (0.5 mg/kg i.v.). Our results suggest that cannabinoid CB2 agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system (CNS) side-effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain.
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影响因子：
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