Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.
Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.
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DOI：
10.1371/journal.pone.0096396
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sagen J
中科院分区：
文献类型：
--
作者：
Hama AT;Germano P;Varghese MS;Cravatt BF;Milne GT;Pearson JP;Sagen J
神经性脊髓损伤（SCI）疼痛的改善是一个临床挑战。通过阻断脂肪酸酰胺水解酶（FAAH）来增加内源性大麻素anandamide和其他脂肪酸酰胺（FAA）已被证明在许多慢性疼痛的动物模型中具有抗伤害感受性。然而，阻断FAAH的抗伤害效应尚未在神经性SCI疼痛的大鼠模型中得到证实。SCI后四周，大鼠后爪缩回阈值显著降低，表明低于水平的皮肤超敏反应。将一组SCI大鼠全身处理（i. p.）与选择性FAAH抑制剂URB 597或媒介物一起，每天两次，持续7天。另一组SCI大鼠接受单剂量（p.o.）选择性FAAH抑制剂PF-3845或赋形剂。在行为测试之后，定量来自SCI大鼠的脑和脊髓中的FAA N-花生四烯酰乙醇酰胺、N-油酰乙醇酰胺和N-棕榈酰乙醇酰胺的水平。SCI后4周，脊髓组织中FAA水平显著降低。尽管用URB 597的全身治疗显著增加CNS FAA水平，但未观察到抗伤害感受作用。PF-3845口服给药后还观察到CNS FAA水平显著升高，但仅观察到中度抗伤害效应。单独增加CNS FAA水平不会导致低于水平的神经性SCI疼痛的稳健改善。也许利用FAAH抑制与其他镇痛机制结合可能是一种有效的镇痛治疗。
Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.
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影响因子：
4.7
作者：
Gwak, Young S.;Hulsebosch, Claire E.
通讯作者：
Hulsebosch, Claire E.
DOI：
10.1523/jneurosci.2428-10.2010
发表时间：
2010-11-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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Walters ET
DOI：
10.1124/jpet.111.180257
发表时间：
2011-07-01
影响因子：
3.5
作者：
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通讯作者：
Cravatt, Benjamin F.
影响因子：
4.2
作者：
Christensen, MD;Hulsebosch, CE
通讯作者：
Hulsebosch, CE
影响因子：
4.5
作者：
Ahmed, Mostafa M.;Rajpal, Sharad;Resnick, Daniel K.
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