n-oleoylglycine and Morphine-Dependence

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. These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Topics: Animals; Female; Glycine; Male; Medically Unexplained Symptoms; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Nausea; Oleic Acids; Rats; Rats, Sprague-Dawley; Shrews; Substance Withdrawal Syndrome

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. Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.

Topics: Alanine; Analgesics, Opioid; Animals; Glycine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Oleic Acids; Rats; Rats, Sprague-Dawley; Reward; Substance Withdrawal Syndrome