Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine

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.…”

“…Additionally, AEA mobilization and the mRNA levels of the PPARα receptor were elevated in the spinal cord of morphine tolerant mice (Fotio et al, 2020). Since OlGly and OlAla interfere with naloxone-precipitated MWD by both CB 1 and PPARα antagonism (Ayoub et al, 2020;Rock et al, 2020), we predicted that OlGly and OlAla would also interfere with tolerance to morphine as does URB597 (Fotio et al, 2020). The lack of an effect on tolerance to morphine may have been a function of the relatively weak efficacy of OlGly to inhibit FAAH (IC 50 = 8.65 µM; Donvito et al, 2019) relative to the more potent FAAH inhibitor, URB597 (4.6 nM; Mor et al, 2004).…”

“…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).…”

Cannabinoid treatment of opiate addiction

“…FAAH inhibitors, including URB-597 and PF-3845, reduce withdrawal symptoms in morphine-dependent mice and rats [46,97,98]. Recently, N-oleoylglycine (OlGly), a fatty acid amide which appears to act as a FAAH inhibitor and a peroxisome proliferator-activated receptor alpha (PPARα) agonist, limited naloxone-precipitated morphine withdrawal symptoms in male rats, including abdominal contractions, lying on belly, diarrhoea and mouthing movements [99]. The effects of OlGly on morphine withdrawal were mediated by CB1R and PPARα [99], indicating that increasing endogenous cannabinoid levels could be a potential treatment option for opioid dependence.…”