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

Abstract

The endogenous amide N-Oleoylglycine (OlGly) and its analog N-Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance. Administration of neither OlGly nor OlAla interfered with the establishment of morphine tolerance, nor did they modify behavioral responses elicited by morphine on any trial. These results suggest that the effects of OlGly and OlAla on opiate dependence may be limited to naloxone-precipitated withdrawal effects.

Orally Administered N-Oleoyl Alanine Blocks Acute Opioid Withdrawal Induced-Conditioned Place Preference and Attenuates Somatic Withdrawal following Chronic Opioid Exposure in Rats

“…Importantly, earlier work has not recorded any adverse side-effect of OlAla pretreatment by itself. In fact, when administered alone, OlAla treatment has never interfered with any of the withdrawal behaviors of interest [14,15], and also produces no effect on body temperature, nociception or activity levels in rats [19]. Taken together, these data highlight the therapeutic potential of OlAla.…”

“…Consequently, blocking the activity of either PPARα or the cannabinoid-1 (CB 1 ) receptor reverses OlGly's effects on acute opioid withdrawal behavior [12,16]. Despite its effects on the CB 1 receptor, OlGly does not produce any of the negative side effects associated with cannabimimetic activity [10,19], which is also important to consider during the development of pharmacotherapies. However, OlGly is short-lasting in the body as it is rapidly inactivated by degrading enzymes and may therefore be a poor candidate to develop for human clinical trials.…”

The endocannabinoidome mediator N-oleoylglycine is a novel protective agent against 1-methyl-4-phenyl-pyridinium-induced neurotoxicity

“…The proposed mechanism is through PPARα and by modulating the levels of eCB and eCB-like mediators, possibly via FAAH inhibition. Other effects of OlGly have, in fact, been previously ascribed both to activation of PPARα and inhibition of FAAH (Rock et al, 2021). Moreover, the present study investigated the functional features of the eCB system systematically either in not differentiated and differentiated SH-SY5Y cells treated with MPP + , a piece of information that was missing in the literature.…”

A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology

“…Hence, we synthesized a derivative, oleoyl alanine (OlAla), in which the amide bond is somewhat protected (55). Indeed, we noted that OlAla, which turned out to also be an endogenous molecule, was a more stable and effective treatment for opiate withdrawal than was OlGly (55,56). OlAla was effective in reducing opioid withdrawal responses in rats experiencing both acute and chronic opioid withdrawal.…”