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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Ahn K, McKinney MK, Cravatt BF (2008) Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev 108(5):1687–1707
Arreaza G, Devane WA, Omeir RL, Sajnani G, Kunz J, Cravatt BF, Deutsch DG (1997) The cloned rat hydrolytic enzyme responsible for the breakdown of anandamide also catalyzes its formation via the condensation of arachidonic acid and ethanolamine. Neurosci Lett 234:59–62
Bhargava HN (1976a) Inhibition of naloxone-induced withdrawal in morphine dependent mice by l-trans-Δ9-tetrahydrocannabinol. Eur J Pharmacol 36:259–262
Bhargava HN (1976b) Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-thetrahydrocannabinol. Eur J Pharmacol 36:259–262
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 21:859–872
Bisogno T, Sepe N, De Petrocellis L, Di Marzo V (1997) Biosynthesis of 2-arachidonyl-glycerol, a novel cannabimimetic eicosanoid, in mouse neuroblastoma cells. Adv Exp Med Biol 433:201–204
Bradshaw HB, Rimmerman N, Hu SSJ, Burstein S, Walker JM (2009) Novel endogenous N-acyl glycines. Identification and characterization. Vitam Horm 81:191–205
Burstein SH, McQuain CA, Ross AH, Salmonsen RA, Zurier RE (2011) Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem 112:3227–3233
Cohen-Yeshurun A, Trembovler V, Alexandrovich A, Ryberg E, Greasley PJ, Mechoulam R, Shohami E, Leker RR (2011) N-arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J Cereb Blood Flow Metab 31:1768–1777
Contreras M, Ceric F, Torrealba F (2007) Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 318:655–658
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
Devane WA, Hanuš L, Breuer A, Pertwee RG, Lesley A, Griffin G, Gibson D, Mandelbaum A, Etinger A, Stevenson LA (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824
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 148:320–321
Eisenberg RM (1982) Further studies on the acute dependence produced by morphine in opiate naive rats. Life Sci 31:1531–1540
Gamage TF, Ignatowska-Jankowska BM, Muldoon PP, Cravatt BF, Damaj MI, Lichtman AH (2015) Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice. Drug Alcohol Depend 146:7–16
Gellert VF, Sparber SB (1977) A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine-dependent rats. J Pharmacol Exp Ther 201:44–54
Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1990) Acute opioid physical dependence in humans: effect of naloxone at 6 and 24 hours postmorphine. Pharmacol Biochem Behav 36:393–399
Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TTY, Gray JM, Hillard CJ, Gorzalka BB, Viau V (2010) Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci U S A 107:9406–9411
Higgins GA, Sellers EM (1994) Antagonist-precipitated opioid withdrawal in rats: evidence for dissociations between physical and motivational signs. Pharmacol Biochem Behav 48:1–8
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 276:42639–42644
June HL, Stitzer ML, Cone E (1995) Acute physical dependence: time course and relation to human plasma morphine concentrations. Clin Pharmacol Ther 57:270–280
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 40:2185–2197
Koob GF (2009a) Brain stress systems in the amygdala and addiction. Brain Res 1293:61–75
Koob GF (2009b) Dynamics of neuronal circuits in addiction: reward, antireward, and emotional memory. Pharmacopsychiatry 42(Suppl 1):S32–S41
Li CL, Zhu N, Meng XL, Li YH, Sui N (2013) Effects of inactivating the agranular or granular insular cortex on the acquisition of the morphine-induced conditioned place preference and naloxone-precipitated conditioned place aversion in rats. J Psychopharmacol 27:837–844
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 15:277–288
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 94:154–162
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascioll MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534
Martin WR, Eades CG (1964) A comparison between acute and chronic physical dependence in the chronic spinal dog. J Pharmacol Exp Ther 146:385–394
Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan RK, Johnson MR, Melvin LS, Mechoulam R, Ward SJ (1991) Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 40:471–478
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 69:633–641
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 96:496–500
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 50:83–90
Naidu PS, Varvel SA, Ahn K, Cravatt BF, Martin BR, Lichtman AH (2007) Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology 192:61–70
Naqvi NH, Rudrauf D, Damasio H, Bechara A (2007) Damage to the insula disrupts addiction to cigarette smoking. Science 315:531–534
Parker LA, Cyr JA, Santi AN, Burton PD (2002) The aversive properties of acute morphine dependence persist 48 h after a single exposure to morphine: evaluation by taste and place conditioning. Pharmacol Biochem Behav 72:87–92
Parker LA, Joshi A (1998) Naloxone-precipitated morphine withdrawal induced place aversions: effect of naloxone at 24 hours postmorphine. Pharmacol Biochem Behav 61:331–333
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 339:173–185
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 232:3841–3848
Rock EM, Guillermo MS, Limebeer CL, Petrie G, Angelini R, Piomelli D, Parker LA (2017) Suppression of acute and anticipatory nausea by peripherally restricted FAAH inhibitor in animal models: role of PPARa and CB1 receptors. Br J Pharmacol 174:3837–3847
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 54:129–140
Schulteis G, Markou A, Gold LH, Stinus L, Koob GF (1994) Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantiative dose-response analysis. J Pharmacol Exp Ther 271:1391–1398
Shoblock JR, Maidment NT (2006) Constitutively active mu opioid receptors mediate the enhanced conditioned aversvie effect of naloxone in morphine-dependent mice. Neuropsychopharmacology 31:171–177
Sulcova E, Mechoulam R, Fride E (1998) Biphasic effects of anandamide. Pharmacol Biochem Behav 59:347–352
Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH (2007) Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32:1032–1041
Vela G, Ruiz-Gayo M, Fuentes JA (1995) Anandamide decreases naloxone-precipitated withdrawal signs in mice chronically treated with morphine. Neuropharmacology 34:665–668
Wills KL, Parker LA (2016) Effect of pharmacological modulation of the endocannabinoid system on opiate withdrawal: a review of the preclinical animal literature. Front Pharmacol 7:1–9
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 41:1865–1873
Wills KL, Vemuri K, Kalmar A, Lee A, Limebeer CL, Makriyannis A, Parker LA (2014) CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats. Psychopharmacology 231:4291–4300
Wise LE, Harloe JP, Lichtman AH (2009) Fatty acid amide hydrolase (FAAH) knockout mice exhibit enhanced acquisition of an aversive, but not of an appetitive, Barnes maze task. Neurobiol Learn Mem 92:597–601
Yamaguchi T, Hagiwara Y, Tanaka H, Sugiura T, Waku K, Shoyama Y, Watanabe S, Yamamoto T (2001) Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice. Brain Res 909:121–126
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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Petrie, G.N., Wills, K.L., Piscitelli, F. et al. Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague–Dawley rats. Psychopharmacology 236, 2623–2633 (2019). https://doi.org/10.1007/s00213-019-05237-9
- 2-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)