Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, Israel.
Psychopharmacology (Berl). 2020 Feb;237(2):375-384. doi: 10.1007/s00213-019-05373-2. Epub 2019 Nov 11.
Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats.
The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses.
Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB and PPARα mediated.
These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.
急性纳洛酮诱发的吗啡戒断（MWD）会在大鼠中产生条件性位置厌恶（CPA），即使大鼠只暴露于两次高剂量（20mg/kg，sc）吗啡，24 小时后给予纳洛酮（1mg/kg，sc）也是如此。然而，急性纳洛酮诱发的 MWD 在大鼠中产生的躯体戒断反应尚未得到研究。一种最近发现的脂肪酸酰胺，N-油酰基甘氨酸（OlGly），被认为可以作为脂肪酸酰胺水解酶（FAAH）抑制剂和过氧化物酶体增殖物激活受体α（PPARα）激动剂，先前已被证明可以干扰纳洛酮诱发的 MWD 诱导的大鼠 CPA。
这些研究的目的是检查急性纳洛酮诱发的 MWD 引起的躯体戒断反应，并确定 OlGly 是否也可以干扰这些反应。
在这里，我们报告说，在两次暴露于吗啡（20mg/kg，sc）后，每次都在 24 小时后给予纳洛酮（1mg/kg，sc），大鼠表现出类似于恶心的躯体反应，如腹部平坦、腹部收缩和腹泻，以及增加的口部运动和体重减轻。OlGly（5mg/kg，ip）通过大麻素 1（CB）和 PPARα 作用机制干扰纳洛酮诱发的 MWD 诱导的腹部收缩、腹部平坦、腹泻和口部运动。由于这些戒断反应是恶心的症状，我们评估了 OlGly 干扰氯化锂（LiCl）诱导和 MWD 诱导的大鼠条件性张口的潜力，这是一种选择性的恶心测量方法；OlGly 对 MWD 诱导的张口反应的抑制作用是 CB 和 PPARα 介导的。
这些结果表明，急性纳洛酮诱发的 MWD 的厌恶效应反映了恶心，而 OlGly 可以抑制这种恶心。
