Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats

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

“…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.…”

“…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). Similar to OlGly, OlAla weakly inhibited FAAH by about 40% at 10 µM (Ayoub et al, 2020). Unfortunately, neither FAAH activity nor AEA levels were measured in the tissue of these animals.…”

“…Chronic dosing of morphine (twice daily 20 mg/kg, except day 1, for 13 days) resulted in tolerance to the hypolocomotor and the anti-nociceptive, but not to the hyperthermic, effects of morphine, as has been reported to the anti-nociceptive effects of morphine by Fotio et al (2020). Here rats were injected with OlGly (5 mg/kg, ip, Experiment 1) or OlAla (5 mg/kg ip, Experiment 2) prior to each chronic treatment with morphine or saline to determine if these fatty acid amides that act in vitro as FAAH inhibitors and PPARα agonists (Donvito et al, 2019;Ayoub et al, 2020), would interfere with morphine tolerance as has been reported for the FAAH inhibitor, URB597 (Fotio et al, 2020). 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.…”

“…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).…”

“…Because endogenous OlGly is rapidly deactivated by amidases, a more stable analog, N-oleoylalanine (OlAla), was synthesized by Mechoulam's group. OlAla, which is also an endogenous lipid (Bradshaw et al, 2009), also interfered with the affective symptoms of acute naloxone-precipitated MWD, but it was effective for a longer duration than OlGly through a CB 1 receptor and PPARα -dependent mechanism (Ayoub et al, 2020). Accordingly, OlAla was found to inhibit FAAH and activate PPARα in vitro.…”