Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Institute of Drug Research, Medical Faculty, Hebrew University of Jerusalem, Jerusalem, Israel.
Psychopharmacology (Berl). 2020 Sep;237(9):2753-2765. doi: 10.1007/s00213-020-05570-4. Epub 2020 Jun 16.
Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal.
The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated.
Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference.
Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.
油酰甘氨酸是一种结构上与大麻素类似的研究较少的脂肪酸酰胺，它可以干扰小鼠对尼古丁的成瘾和大鼠急性纳洛酮引发的吗啡戒断（MWD）。由于内源性油酰甘氨酸容易被快速酶失活，我们评估了更稳定的类似物干扰阿片类药物戒断的潜力。
评估单甲基化油酰甘氨酸（油酰丙氨酸，HU595）干扰急性纳洛酮引发的 MWD 的躯体和厌恶效应、其持续时间及其作用机制的潜力，在雄性 Sprague Dawley 大鼠中进行评估。还研究了二甲基化油酰甘氨酸（HU596）干扰纳洛酮引发的 MWD 的厌恶效应的潜力。
油酰丙氨酸（HU595）以与我们之前报道的油酰甘氨酸相同的剂量（1 和 5mg/kg，ip）干扰纳洛酮引发的 MWD 产生的躯体和厌恶效应；然而，油酰丙氨酸产生的干扰作用持续时间更长（60 分钟），但本身没有产生奖赏或厌恶作用，也不改变运动活动。HU596 无效。PPARα 拮抗剂和 CB 受体拮抗剂均可阻止油酰丙氨酸对纳洛酮引发的 MWD 的厌恶效应的干扰。因此，该化合物被发现可在体外抑制 FAAH 并激活 PPARα。最后，油酰丙氨酸还减少了急性纳洛酮引发的 MWD 的快感缺失，表现为蔗糖偏好降低。
油酰丙氨酸（也是一种内源性脂肪酸）可能是一种比油酰甘氨酸更稳定有效的阿片类药物戒断治疗方法。
