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Open Access 01-12-2022 | Migraine | Research

Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine

Authors: Rosaria Greco, Chiara Demartini, Anna Maria Zanaboni, Miriam Francavilla, Angelo Reggiani, Natalia Realini, Rita Scarpelli, Daniele Piomelli, Cristina Tassorelli

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Targeting fatty acid amide hydrolase (FAAH) is a promising therapeutic strategy to combat certain forms of pain, including migraine headache. FAAH inhibitors, such as the O-biphenyl-3-yl carbamate URB597, have been shown to produce anti-hyperalgesic effects in animal models of migraine. The objective of this study was to investigate the behavioral and biochemical effects of compounds ARN14633 and ARN14280, two URB597 analogs with improved solubility and bioavailability, in a migraine-specific rat model in which trigeminal hyperalgesia is induced by nitroglycerin (NTG) administration. ARN14633 (1 mg/kg, i.p.) and ARN14280 (3 mg/kg, i.p.) were administered to adult male Sprague-Dawley rats 3 hours after NTG injection. One hour after the administration of either compound, rats were subjected to the orofacial formalin test. ARN14633 and ARN14280 attenuated NTG-induced nocifensive behavior and reduced transcription of genes encoding neuronal nitric oxide synthase, pain mediators peptides (calcitonin gene-related peptide, substance P) and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and 6) in the trigeminal ganglion, cervical spinal cord and medulla. Finally, both compounds strongly elevated levels of endocannabinoids and/or other FAAH substrates in cervical spinal cord and medulla, and, to a lesser extent, in the trigeminal ganglia. The results indicate that the novel global FAAH inhibitors ARN14633 and ARN14280 elicit significant anti-hyperalgesic effects in a migraine-specific animal model and inhibit the associated peptidergic-inflammatory response. Although the precise mechanism underlying these effects remains to be elucidated, our results support further investigational studies of FAAH blockade as a potential therapeutic strategy to treat migraine conditions.

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Greco R, Demartini C, Zanaboni AM, Piomelli D, Tassorelli C (2018) Endocannabinoid system and migraine pain: an update. Front Neurosci 12:172. https://doi.org/10.3389/fnins.2018.00172CrossRefPubMedPubMedCentral

Greco R, Demartini C, Zanaboni AM, Tumelero E, Reggiani A, Misto A, Piomelli D, Tassorelli C (2020) FAAH inhibition as a preventive treatment for migraine: a pre-clinical study. Neurobiol Dis 134:104624. https://doi.org/10.1016/j.nbd.2019.104624CrossRefPubMed

Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270(11):6030–6035. https://doi.org/10.1074/jbc.270.11.6030CrossRefPubMed

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(6604):83–87. https://doi.org/10.1038/384083a0CrossRefPubMed

Cravatt BF, Lichtman AH (2004) The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol 61(1):149–160. https://doi.org/10.1002/neu.20080CrossRefPubMed

Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D (2005) The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67(1):15–19. https://doi.org/10.1124/mol.104.006353CrossRefPubMed

LoVerme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, Meli R, Hohmann A, Calignano A, Piomelli D (2006) Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther 319(3):1051–1061. https://doi.org/10.1124/jpet.106.111385CrossRefPubMed

Pontis S, Ribeiro A, Sasso O, Piomelli D (2016) Macrophage-derived lipid agonists of PPAR-α as intrinsic controllers of inflammation. Crit Rev Biochem Mol Biol 51(1):7–14. https://doi.org/10.3109/10409238.2015.1092944CrossRefPubMed

Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9(1):76–81. https://doi.org/10.1038/nm803CrossRefPubMed

10.

Tarzia G, Duranti A, Tontini A, Piersanti G, Mor M, Rivara S, Plazzi PV, Park C, Kathuria S, Piomelli D (2003) Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors. J Med Chem 46(12):2352–2360. https://doi.org/10.1021/jm021119gCrossRefPubMed

11.

Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci U S A 102(51):18620–18625. https://doi.org/10.1073/pnas.0509591102CrossRefPubMedPubMedCentral

12.

Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2007) Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62(10):1103–1110. https://doi.org/10.1016/j.biopsych.2006.12.001CrossRefPubMed

13.

Panlilio LV, Justinova Z, Goldberg SR (2013) Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacol Ther 138(1):84–102. https://doi.org/10.1016/j.pharmthera.2013.01.003CrossRefPubMedPubMedCentral

14.

Scherma M, Panlilio LV, Fadda P, Fattore L, Gamaleddin I, Le Foll B, Justinová Z, Mikics E, Haller J, Medalie J, Stroik J, Barnes C, Yasar S, Tanda G, Piomelli D, Fratta W, Goldberg SR (2008) Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther 327(2):482–490. https://doi.org/10.1124/jpet.108.142224CrossRefPubMed

15.

Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D (2006) Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12(1):21–38. https://doi.org/10.1111/j.1527-3458.2006.00021.xCrossRefPubMedPubMedCentral

16.

Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147(3):281–288. https://doi.org/10.1038/sj.bjp.0706510CrossRefPubMed

17.

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(9):2185–2197. https://doi.org/10.1038/npp.2015.62CrossRefPubMedPubMedCentral

18.

Mascia P, Pistis M, Justinova Z, Panlilio LV, Luchicchi A, Lecca S, Scherma M, Fratta W, Fadda P, Barnes C, Rdhi 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(7):633–641. https://doi.org/10.1016/j.biopsych.2010.07.009CrossRefPubMedPubMedCentral

19.

Russo R, LoVerme J, La Rana G, Compton TR, Parrott J, Duranti A, Tontini A, Mor M, Tarzia G, Calignano A, Piomelli D (2007) The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther 322(1):236–242. https://doi.org/10.1124/jpet.107.119941CrossRefPubMed

20.

Okine BN, Norris LM, Woodhams S, Burston J, Patel A, Alexander SP, Barrett DA, Kendall DA, Bennett AJ, Chapman V (2012) Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system. Br J Pharmacol 167(3):627–640. https://doi.org/10.1111/j.1476-5381.2012.02028.xCrossRefPubMedPubMedCentral

21.

Hama AT, Germano P, Varghese MS, Cravatt BF, Milne GT, Pearson JP, Sagen J (2014) Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain. PLoS One 9(5):e96396. https://doi.org/10.1371/journal.pone.0096396CrossRefPubMedPubMedCentral

22.

Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16(2):109–110. https://doi.org/10.1016/0304-3959(83)90201-4CrossRefPubMed

23.

Greco R, Bandiera T, Mangione AS, Demartini C, Siani F, Nappi G, Sandrini G, Guijarro A, Armirotti A, Piomelli D, Tassorelli C (2015) Effects of peripheral FAAH blockade on NTG-induced hyperalgesia--evaluation of URB937 in an animal model of migraine. Cephalalgia 35(12):1065–1076. https://doi.org/10.1177/0333102414566862CrossRefPubMed

24.

Greco R, Demartini C, Zanaboni AM, Casini I, De Icco R, Reggiani A, Misto A, Piomelli D, Tassorelli C (2021) Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine. Neurobiol Dis 147:105157. https://doi.org/10.1016/j.nbd.2020.105157CrossRefPubMed

25.

Panlilio LV, Thorndike EB, Nikas SP, Alapafuja SO, Bandiera T, Cravatt BF, Makriyannis A, Piomelli D, Goldberg SR, Justinova Z (2016) Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology 233(10):1879–1888. https://doi.org/10.1007/s00213-015-4140-6CrossRefPubMed

26.

Nozaki C, Markert A, Zimmer A (2015) Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice. Eur Neuropsychopharmacol 25(8):1388–1396. https://doi.org/10.1016/j.euroneuro.2015.04.001CrossRefPubMed

27.

Greco R, Demartini C, Zanaboni AM, Redavide E, Pampalone S, Toldi J, Fülöp F, Blandini F, Nappi G, Sandrini G, Vécsei L, Tassorelli C (2017) Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: targets and anti-migraine mechanisms. Cephalalgia 37(13):1272–1284. https://doi.org/10.1177/0333102416678000CrossRefPubMed

28.

Demartini C, Tassorelli C, Zanaboni AM, Tonsi G, Francesconi O, Nativi C, Greco R (2017) The role of the transient receptor potential ankyrin type-1 (TRPA1) channel in migraine pain: evaluation in an animal model. J Headache Pain 18(1):94. https://doi.org/10.1186/s10194-017-0804-4CrossRefPubMedPubMedCentral

29.

Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A (2010) Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 13(10):1265–1270. https://doi.org/10.1038/nn.2632CrossRefPubMedPubMedCentral

30.

Astarita G, Piomelli D (2009) Lipidomic analysis of endocannabinoid metabolism in biological samples. J Chromatogr B Anal Technol Biomed Life Sci 877(26):2755–2767. https://doi.org/10.1016/j.jchromb.2009.01.008CrossRef

31.

Di Marzo V (2018) New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov 17(9):623–639. https://doi.org/10.1038/nrd.2018.115CrossRefPubMed

32.

Iannotti FA, Piscitelli F (2018) In: eLS (ed) Endocannabinoidome. John Wiley & Sons, ltd, Chichester

33.

Ahn K, Johnson DS, Cravatt BF (2009) Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discovery 4(7):763–784. https://doi.org/10.1517/17460440903018857CrossRef

34.

Pertwee RG (2014) Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc Nutr Soc 73(1):96–105. https://doi.org/10.1017/S0029665113003649CrossRefPubMed

35.

Greco R, Demartini C, Zanaboni AM, Francavilla M, De Icco R, Ahmad L, Tassorelli C (2022) The endocannabinoid system and related lipids as potential targets for the treatment of migraine-related pain. Headache 62(3):227–240. https://doi.org/10.1111/head.14267CrossRefPubMed

36.

Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16(1):9–29. https://doi.org/10.1038/s41582-019-0284-zCrossRefPubMed

37.

Murillo-Rodríguez E, Vázquez E, Millán-Aldaco D, Palomero-Rivero M, Drucker-Colin R (2007) Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat. Eur J Pharmacol 562(1–2):82–91. https://doi.org/10.1016/j.ejphar.2007.01.076CrossRefPubMed

38.

Soria-Gómez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospéro-García O (2007) Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 151(7):1109–1116. https://doi.org/10.1038/sj.bjp.0707313CrossRefPubMedPubMedCentral

39.

Greco R, Demartini C, Francavilla M, Zanaboni AM, Tassorelli C (2021) Dual inhibition of FAAH and MAGL counteracts migraine-like pain and behavior in an animal model of migraine. Cells 10(10):2543. https://doi.org/10.3390/cells10102543CrossRefPubMedPubMedCentral

40.

Paulus MP, Stein MB, Simmons AN, Risbrough VB, Halter R, Chaplan SR (2021) The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial. Neuropsychopharmacology 46(5):1011–1019. https://doi.org/10.1038/s41386-020-00936-wCrossRefPubMed

41.

Deng H, Li W (2020) Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders. Acta Pharm Sin B 10(4):582–602. https://doi.org/10.1016/j.apsb.2019.10.006CrossRefPubMed

Title: Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine
Authors: Rosaria Greco
Chiara Demartini
Anna Maria Zanaboni
Miriam Francavilla
Angelo Reggiani
Natalia Realini
Rita Scarpelli
Daniele Piomelli
Cristina Tassorelli
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Migraine
Nitroglycerin
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-022-01449-1

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Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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