Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague–Dawley rats
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Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice.
Objectives and methods
Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague–Dawley rats.
Synthetic OlGly (1–30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated.
Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.
Keywords2-Arachidonyl glycerol (2-AG) N-Arachidonoyl glycine (AraGly) Anandamide (AEA) Conditioned place aversion (CPA) Fatty acid amide hydrolase (FAAH) Oleoyl glycine (OlGly) Oleoylethanolamide (OEA) Palmitoylethanolamide (PEA) Morphine withdrawal (MWD)
GP, KW, ER, MS, and AH performed behavioral experiments. FP and VD performed the molecular analyses. RS and RM synthesized OlGly. CL prepared all drugs and collected all tissues. GP, KW, AL, VD, RM, and LP designed the experiments and wrote the manuscript.
The research reported here was funded by research grants from the Natural Sciences and Engineering Research Council (NSERC 920157) and the Canadian Institutes for Health Research (CIHR 388239) to LAP, NIH grants R01DA039942, P30DA033934, and VCU School of Pharmacy start-up funds to AHL.
Compliance with ethical standards
All animal procedures were approved by the Animal Care Committee of the University of Guelph and adhere to the guidelines of the Canadian Council of Animal Care.
Conflict of interest
The authors declare that they have no conflict of interest.
- Bilbao A, Serrano A, Cippitelli A, Pavón FJ, Giuffrida A, Suárez J, Garcia-Marchena N, Baixeras E, Gomez de Heras R, Ciccocioppo R, Cravatt BF, Parsons LH, Piomelli D, Rodriguez de Fonseca F (2016) Role for the satiety factor Oleoylethanolamide in alcoholism. Addict Biol 21:859–872CrossRefPubMedGoogle Scholar
- Donvito G, Piscitelli F, Muldoon P, Jackson A, Vitale RM, D’Aniello E, Giordano C, Ignatowska-Jankowska BM, Mustafa MA, Guida F, Petrie GN, Parker L, Smoum R, Sim-Selley L, Maione S, Lichtman AH, Damaj MI, Di Marzo V, Mechoulam R (2019) N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice. Neuropharmacology 148:320–321Google Scholar
- Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L et al (2001) Identification of a new class of molecules, the arachidonyl amino acids,and characterization of one member that inhibits pain. J Biol Chem 276:42639–42644CrossRefPubMedGoogle Scholar
- Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME, Mascia P, Bandiera T, Armirotti A, Bertorelli R, Chefer SI, Barnes C, Yasar S, Piomelli D, Goldberg SR (2015) Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40:2185–2197CrossRefPubMedPubMedCentralGoogle Scholar
- Luchicchi A, Lecca S, Carta S, Pillolla G, Muntoni AL, Yasar S, Goldberg SR, Pistis M (2010) Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-α nuclear receptors. Addict Biol 15:277–288CrossRefPubMedPubMedCentralGoogle Scholar
- Manwell LA, Satvat E, Lang ST, Allen CP, Leri F, Parker LA (2009) FAAH inhibitor, URB-597, promotes extinction and CB1 antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not extinction of conditioned preference produced by morphine in rats. Pharmacol Biochem Behav 94:154–162CrossRefPubMedGoogle Scholar
- Mascia P, Pistis M, Justinova Z, Panlilio LV, Luchicchi A, Lecca S, Scherma M, Fratta W, Fadda P, Barnes C, Redhi GH, Yasar S, Le Foll B, Tanda G, Piomelli D, Goldberg SR (2011) Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry 69:633–641CrossRefPubMedPubMedCentralGoogle Scholar
- McCallum AL, Limebeer CL, Parker LA (2010) Reducing endocannabinoid metabolism with the fatty acid amide hydrolaseinhibitor, URB597, fails to modify reinstatement of morphine-induced conditioned floor preference and naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance. Pharmacol Biochem Behav 96:496–500CrossRefPubMedGoogle Scholar
- Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90CrossRefPubMedGoogle Scholar
- Ramesh D, Ross GR, Schlosburg JE, Owens R, Abdullah R, Kinsey SG, Long JZ, Nomura DK, Sim-Selley LJ, Cravatt BF, Akbarali HI, Lichtman AH (2011) Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther 339:173–185CrossRefPubMedPubMedCentralGoogle Scholar
- Rock EM, Limebeer CL, Ward JM, Cohen A, Grove K, Niphakis MJ, Cravatt BF, Parker LA (2015) Fatty acid amide hydrolase (FAAH) inhibition interferes with acute nausea by a PPARα mechanism and anticipatory nausea by a CB1 receptor mechanism in a double dissociation. Psychopharmacology 232:3841–3848CrossRefPubMedGoogle Scholar
- Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A, Piomelli D, Mikics E, Haller J, Yasar S, Tanda G, Goldberg SR (2008) The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54:129–140CrossRefPubMedGoogle Scholar
- Wills KL, Petrie GN, Millett G, Limebeer CL, Rock EM, Niphakis MJ, Cravatt BF, Parker LA (2016) Double dissociation of monoacylglycerol lipase inhibition and CB1 antagonism in the central amygdala, basolateral amygdala, and the interoceptive insular cortex on the affective properties of acute naloxone-precipitated morphine withdrawal in rats. Neuropsychopharmacology 41:1865–1873CrossRefPubMedPubMedCentralGoogle Scholar