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

Erin M Rock,Marieka V Devuono,Raphael Mechoulam,Aron H Lichtman,Cheryl L Limebeer,Vincenzo Di Marzo,Linda A Parker,Megan T Sullivan

doi:10.3389/fnsyn.2021.620145

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.

Highlights

N-Oleoylglycine (OlGly) is an endogenous fatty acid amide that is structurally similar to Naceylethanolamines, including the endocannabinoid, anandamide (AEA), as well as the endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists, N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA)
Chronic dosing of morphine 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)
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)

Summary

Introduction

N-Oleoylglycine (OlGly) is an endogenous fatty acid amide that is structurally similar to Naceylethanolamines, including the endocannabinoid, anandamide (AEA), as well as the endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists, N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). Endogenous OlGly is released in the insular cortex of mice experiencing traumatic brain injury (Donvito et al, 2019). Since the insular cortex is a site critical for nicotine addiction (Naqvi et al, 2007, 2014; Forget et al, 2010), the laboratory of Raphael Mechoulam synthesized OlGly for evaluation of the potential of this fatty acid to mitigate nicotine addiction. Did not bind with cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptors in vitro and did not produce the typical CB1 receptor tetrad (antinociception, hypothermia, catalepsy, and hypomobility) of behaviors in mice. Was shown to bind with PPARα and to inhibit fatty

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