Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy.
Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy.
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DOI：
10.1016/j.neuropharm.2014.11.024
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发表时间：
2015-08
影响因子：
4.7
通讯作者：
Sagen J
中科院分区：
文献类型：
--
作者：
Nasirinezhad F;Jergova S;Pearson JP;Sagen J
远端感觉神经病变是艾滋病毒感染的一个标志，尽管抗逆转录病毒疗法取得了进展，但仍可能导致持续性和致残性疼痛。 HIV 感觉神经性 (HIV-SN) 疼痛可能适合大麻素治疗，但目前可用的激动剂治疗因不良副作用和在该患者群体中滥用的可能性而受到限制。脂肪酸酰胺水解酶 (FAAH) 抑制剂可能提供一种替代方法，通过抑制内源性大麻素的降解，据称减少不良中枢神经系统副作用。为了评估这种治疗 HIV-SN 疼痛的潜在方法，将重组 HIV 包膜蛋白 gp120 应用于大鼠坐骨神经外膜，以诱导 HIV-SN 样疼痛综合征。测试了两种不同的 FAAH 抑制化合物 URB597 和 PF-3845，并与标准镇痛加巴喷丁或载体治疗进行对比，以减轻触觉异常性疼痛、冷异常性疼痛和机械性痛觉过敏。两种 FAAH 抑制剂均能显着减轻冷痛和触觉异常性疼痛，但抗痛觉过敏作用有限。在减少触觉异常性疼痛方面，两种药物产生的峰值镇痛作用比加巴喷丁更温和，但效力范围相似。 URB597 产生与加巴喷丁相当的冷抗异常疼痛作用，并且两种 FAAH 抑制剂的作用比加巴喷丁更持久。为了评估大麻素受体在这些抗伤害作用中的贡献，将 CB1 拮抗剂 AM251 或 CB2 拮抗剂 SR144528 与 FAAH 抑制剂联合进行了测试。结果表明 CB1 和 CB2 介导的作用都有贡献，特别是在减少触觉异常性疼痛方面。总之，这些发现支持抑制内源性大麻素降解作为治疗致残性持续性 HIV-SN 疼痛综合征的一个有希望的目标。
Distal sensory neuropathies are a hallmark of HIV infections and can result in persistent and disabling pain despite advances in antiretroviral therapies. HIV-sensory neuropathic (HIV-SN) pain may be amenable to cannabinoid treatment, but currently available agonist treatments are limited by untoward side effects and potential for abuse in this patient population. Fatty acid amide hydrolase (FAAH) inhibitors may offer an alternative approach by inhibiting the degradation of endocannabinoids with purportedly fewer untoward CNS side effects. In order to evaluate this potential approach in the management of HIV-SN pain, the recombinant HIV envelope protein gp120 was applied epineurally to the rat sciatic nerve to induce an HIV-SN-like pain syndrome. Two distinct FAAH inhibitory compounds, URB597 and PF-3845 were tested, and contrasted with standard antinociceptive gabapentin or vehicle treatment, for attenuation of tactile allodynia, cold allodynia, and mechanical hyperalgesia. Both FAAH inhibitors markedly reduced cold and tactile allodynia with limited anti-hyperalgesic effects. Peak antinociceptive effects produced by both agents were more modest than gabapentin in reducing tactile allodynia with similar potency ranges. URB597 produced comparable cold anti-allodynic effects to gabapentin, and the effects of both FAAH inhibitors were longer lasting than gabapentin. To assess the contribution of cannabinoid receptors in these antinociceptive effects, CB1 antagonist AM251 or CB2 antagonist SR144528 were tested in conjunction with FAAH inhibitors. Results suggested a contribution of both CB1- and CB2-mediated effects, particularly in reducing tactile allodynia. In summary, these findings support inhibition of endocannabinoid degradation as a promising target for management of disabling persistent HIV-SN pain syndromes.
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