Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague–Dawley rats

N-Oleoylglycine and N-Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine

“…We have previously demonstrated that at a dose of 5 mg/kg, OlGly and OlAla interfere with naloxoneprecipitated withdrawal from acutely administered morphine, without modifying morphine reward (Donvito et al, 2019;Petrie et al, 2019;Ayoub et al, 2020;Rock et al, 2020). Here we show that this effective dose of OlGly and OlAla did not affect the hypolocomotor effect, anti-nociceptive effect or the hyperthermic effect of morphine on any occasion across 13 treatment days and did not modify the development of tolerance to any of these effects.…”

“…However, at least at a dose of 5 mg/kg, ip, neither OlGly nor OlAla administration interfered with the establishment of tolerance to the anti-nocicieptive and the hypolocomotor effects of morphine. These results suggest that, at the most effective dose for interference with acute naloxone-precipitated MWD responses (Petrie et al, 2019;Ayoub et al, 2020;Rock et al, 2020), neither OlGly nor OlAla are likely to prevent the establishment of tolerance to the chronic effects of morphine. However, it is possible that a higher dose of OlGly or OlAla would be required to chronically reduce tolerance than that required to acutely reduce opioid withdrawal.…”

“…At the effective dose of 5 mg/kg, OlGly had no effects on its own in the absence of MWD. Although interference with the affective properties of MWD by OlGly was prevented by pretreatment with a CB 1 receptor antagonist but not a PPARα antagonist (Petrie et al, 2019), interference with somatic MWD responses by OlGly was prevented by either pretreatment with a CB 1 receptor antagonist or a PPARα antagonist (which had no effects on their own). Since OlGly does not strongly bind to CB 1 receptors, the interference with the anti-withdrawal effects of OlGly on CB 1 receptors was most likely mediated by its action as a FAAH inhibitor, and subsequent elevation of endogenous AEA levels.…”

“…Not only has OlGly been shown to interfere with nicotine dependence, but also with the aversive (Petrie et al, 2019) and somatic (Rock et al, 2020) withdrawal produced by acute naloxone-precipitated morphine withdrawal (MWD), at a dose of 1 or 5 mg/kg, intraperitoneal (ip), but not 20 mg/kg, ip, in rats. On the other hand, OlGly neither modified a morphine place preference (also reported in mice by Donvito et al, 2019), nor did it modify reinstatement of a previously extinguished morphine conditioned place preference (Petrie et al, 2019). At the effective dose of 5 mg/kg, OlGly had no effects on its own in the absence of MWD.…”

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

“…The anti-reward effect, assessed in the conditioned place preference (CPP) paradigm, required PPAR-α activation as was reverted by PPAR-α antagonist administration [56]. Moreover, the capability of NOleGly to interfere with the aversive properties associated with acute naloxone-precipitated morphine withdrawal (MWD) and the rewarding effects of morphine in Sprague-Dawley rats has been investigated [57]. NOleGly impacted MWD and the CB 1 antagonist, AM251, but not the PPARα antagonist, MK886, prevented NOleGly effect suggesting a CB 1 receptor-mediating action.…”