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The Journal of Headache and Pain

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Open Access 01-12-2014 | Research article

Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model

Authors: Rosaria Greco, Antonina Stefania Mangione, Giorgio Sandrini, Giuseppe Nappi, Cristina Tassorelli

Published in: The Journal of Headache and Pain | Issue 1/2014

Abstract

Background

Experimental animal models of migraine have suggested the existence of interactions between the endocannabinoid system and pain mediation in migraine. Extensive evidence has demonstrated a role for the cannabinoid-1 (CB1) receptor in antinociception. However, recent research suggests that also CB2 receptors, especially located outside the central nervous system, play a role in the perception of pain. Systemic administration of nitroglycerin (NTG) consistently induces spontaneous-like headache attacks in migraneurs; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. In this study we evaluated the role of CB2 receptors in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia.

Methods

The study was performed in male Sprague-Dawley rats pre-treated with NTG (10 mg/kg, i.p.) or vehicle (4 hours before) and treated with the CB2 agonist AM1241 o dimethylsulfoxide (DMSO) 60 minutes before both the tail flick test and the formalin test.

Results

AM1241 showed a significant analgesic effect in baseline conditions in both tests. Furthermore, when administered 3 hours after NTG administration, AM1241 at both doses significantly reduced the total number of flinches/shakes during phase II of the test.

Conclusion

These findings suggest that the pharmacological manipulation of the CB₂ receptor may represent a potential therapeutic tool for the treatment of migraine.

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Hohman AG, Herkenham M: Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 1999, 92: 1171–1175. 10.1016/S0306-4522(99)00220-1CrossRef

Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998, 75: 111–119. 10.1016/S0304-3959(97)00213-3CrossRefPubMed

Calignano A, La Rana G, Giuffrida A, Piomelli D: Control of pain initiation by endogenous cannabinoids. Nature 1998, 394: 277–281. 10.1038/28393CrossRefPubMed

Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365: 61–65. 10.1038/365061a0CrossRefPubMed

Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 1995, 92: 3376–3380. 10.1073/pnas.92.8.3376PubMedCentralCrossRefPubMed

Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG: International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002, 54: 161–202. 10.1124/pr.54.2.161CrossRefPubMed

Atwood BK, Mackie K: CB₂: a cannabinoid receptor with an identity crisis. Br J Pharmacol 2011, 160: 467–479.CrossRef

Di Marzo V: Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nat Neurosci 2011, 14: 9–15. 10.1038/nn.2720CrossRefPubMed

Romero-Sandoval A, Nutile-McMenemy N, DeLeo JA: Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 2008, 108: 722–734. 10.1097/ALN.0b013e318167af74PubMedCentralCrossRefPubMed

10.

Yao BB, Hsieh GC, Frost JM, Fan Y, Garrison TR, Daza AV, Grayson GK, Zhu CZ, Pai M, Chandran P, Salyers AK, Wensink EJ, Honore P, Sullivan JP, Dart MJ, Meyer MD: In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br J Pharmacol 2008, 153: 390–401. 10.1038/sj.bjp.0707568PubMedCentralCrossRefPubMed

11.

Malan TP Jr, Ibrahim MM, Lai J, Vanderah TW, Makriyannis A, Porreca F: CB₂ cannabinoid receptor-mediated peripheral antinociception. Pain 2001, 3: 239–245.CrossRef

12.

Romero TR, Resende LC, Guzzo LS, Duarte ID: CB1 and CB2 cannabinoid receptor agonists induce peripheral antinociception by activation of the endogenous noradrenergic system. Anesth Analg 2013, 116: 463–472. 10.1213/ANE.0b013e3182707859CrossRefPubMed

13.

Vincenzi F, Targa M, Corciulo C, Tabrizi MA, Merighi S, Gessi S, Saponaro G, Baraldi PG, Borea PA, Varani K: Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models. Pain 2013, 154: 864–873. 10.1016/j.pain.2013.02.007CrossRefPubMed

14.

Greco R, Gasperi V, Maccarrone M, Tassorelli C: The endocannabinoid system and migraine. Exp Neurol 2010, 224(1):85–91. 10.1016/j.expneurol.2010.03.029CrossRefPubMed

15.

Tassorelli C, Joseph SA: Systemic nitroglycerin induces Fos-ir in brainstem and forebrain structures of the rat. Brain Res 1995, 682: 167–178. 10.1016/0006-8993(95)00348-TCrossRefPubMed

16.

Tassorelli C, Greco R, Wang D, Morelli G, Nappi G: Nitroglycerin induces hyperalgesia in rats: a time-course study. Eur J Pharm 2003, 464: 159–162. 10.1016/S0014-2999(03)01421-3CrossRef

17.

Bergerot A, Holland PR, Akerman S, Bartsch T, Ahn AH, MaassenVanDenBrink A, Reuter U, Tassorelli C, Schoenen J, Mitsikostas DD, van den Maagdenberg AM, Goadsby PJ: Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci 2006, 24: 1517–1534. 10.1111/j.1460-9568.2006.05036.xCrossRefPubMed

18.

Tassorelli C, Greco R, Sandrini G, Nappi G: Central components of theanalgesic/antihyperalgesic effect of nimesulide: studies in animal models of pain and hyperalgesia. Drugs 2003, 6: 9–22.CrossRef

19.

Sances G, Tassorelli C, Pucci E, Ghiotto N, Sandrini G, Nappi G: Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia 2000, 24: 110–119.CrossRef

20.

Fanciullacci M, Alessandri M, Sicuteri R, Marabini S: Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 1997, 120(2):283–288. 10.1093/brain/120.2.283CrossRefPubMed

21.

Olesen J, Iversen HK, Thomsen LL: Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 1993, 4(8):1027–1030. 10.1097/00001756-199308000-00008CrossRefPubMed

22.

Greco R, Gasperi V, Sandrini G, Bagetta G, Nappi G, Maccarrone M, Tassorelli C: Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia 2010, 30(3):296–302.PubMed

23.

Greco R, Mangione AS, Sandrini G, Maccarrone M, Nappi G, Tassorelli C: Effects of anandamide in migraine: data from an animal model. J Headache Pain 2011, 12(2):177–183. 10.1007/s10194-010-0274-4PubMedCentralCrossRefPubMed

24.

Greco R, Mangione AS, Siani F, Blandini F, Vairetti M, Nappi G, Sandrini G, Buzzi MG, Tassorelli C: Effects of CGRP antagonism in nitroglycerin-induced hyperalgesia. Cephalalgia 2013. Dec 23. [Epub ahead of print]

25.

Noseda R, Burstein R: Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain 2013. doi:10.1016/j.pain.2013.07.021. [Epub ahead of print]

26.

Tietjen GE, Brandes JL, Peterlin BL, Eloff A, Dafer RM, Stein MR, Drexler E, Martin VT, Hutchinson S, Aurora SK, Recober A, Herial NA, Utley C, White L, Khuder SA: Allodynia in migraine: association with comorbid pain conditions. Headache 2009, 49: 1333–1344. 10.1111/j.1526-4610.2009.01521.xCrossRefPubMed

27.

de Tommaso M, Libro G, Guido M, Difruscolo O, Losito L, Sardaro M, Cerbo R: Nitroglycerin induces migraine headache and central sensitization phenomena in patients with migraine without aura: a study of laser evoked potentials. Neurosci Lett 2004, 363(3):272–275. 10.1016/j.neulet.2004.04.029CrossRefPubMed

28.

Perrotta A, Serrao M, Tassorelli C, Arce-Leal N, Guaschino E, Sances G, Rossi P, Bartolo M, Pierelli F, Sandrini G, Nappi G: Oral nitric-oxide donor glyceryl-trinitrate induces sensitization in spinal cord pain processing in migraineurs: a double-blind, placebo-controlled, cross-over study. Eur J Pain 2011, 15(5):482–490. 10.1016/j.ejpain.2010.09.010CrossRefPubMed

29.

Hsieh GC, Pai M, Chandran P, Hooker BA, Zhu CZ, Salyers AK, Wensink EJ, Zhan C, Carroll WA, Dart MJ, Yao BB, Honore P, Meyer MD: Central and peripheral sites of action for CB₂ receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br J Pharmacol 2011, 162(2):428–440. 10.1111/j.1476-5381.2010.01046.xPubMedCentralCrossRefPubMed

30.

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

31.

Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD, Makriyannis A, Hohmann AG: Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. J Pharmacol Exp Ther 2008, 327(2):584–591. 10.1124/jpet.108.141994PubMedCentralCrossRefPubMed

32.

Tjolsen Aberge OG, Hunskaar S, Rosland JH, Hole K: The formalin test: an evaluation of the method. Pain 1992, 51: 5–17. 10.1016/0304-3959(92)90003-TCrossRef

33.

Martin WJ, Patrick SL, Coffin PO, Tsou K, Walker JM: An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sci 1995, 56(23–24):2103–2109.CrossRefPubMed

34.

Martin WJ, Loo CM, Basbaum AI: Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999, 82(2):199–205. 10.1016/S0304-3959(99)00045-7CrossRefPubMed

35.

Hasanein P, Parviz M, Keshavarz M, Javanmardi K: CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception. Clin Exp Pharmacol Physiol 2007, 34(5–6):439–449.CrossRefPubMed

36.

Katona I, Freund TF: Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 2008, 14(9):923–930. 10.1038/nm.f.1869CrossRefPubMed

37.

Anand P, Whiteside G, Fowler CJ, Hohmann AG: Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev 2008, 60(1):255–266.PubMedCentralCrossRefPubMed

38.

Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G, Molinari M, Maccarrone M: Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci 2009, 29(14):4564–4570. 10.1523/JNEUROSCI.0786-09.2009CrossRefPubMed

39.

Walczak JS, Pichette V, Leblond F, Desbiens K, Beaulieu P: Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain. Neuroscience 2005, 132: 1093–1102. 10.1016/j.neuroscience.2005.02.010CrossRefPubMed

40.

Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A: CB₂ receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 2006, 23: 1530–1538. 10.1111/j.1460-9568.2006.04684.xCrossRefPubMed

41.

Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA: Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005, 310(5746):329–332. 10.1126/science.1115740CrossRefPubMed

42.

Nackley AG, Makriyannis A, Hohmann AG: Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 2003, 119: 747–757. 10.1016/S0306-4522(03)00126-XCrossRefPubMed

43.

Nackley AG, Zvonok AM, Makriyannis A, Hohmann AG: Activation of cannabinoid CB₂ receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol 2004, 92: 3562–3574. 10.1152/jn.00886.2003CrossRefPubMed

44.

Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP Jr: Inhibition of inflammatory hyperalgesia by activation of peripheral CB₂ cannabinoid receptors. Anesthesiology 2003, 99: 955–960. 10.1097/00000542-200310000-00031CrossRefPubMed

45.

Greco R, Tassorelli C, Sandrini G, Di Bella P, Buscone S, Nappi G: Role of calcitonin gene-related peptide and substance P in different models of pain. Cephalalgia 2008, 28(2):114–126.PubMed

46.

Han F, Zhang YF, Li YQ: Fos expression in tyrosine hydroxylase-containing neurons in rat brainstem after visceral noxious stimulation: an immunohistochemical study. World J Gastroenterol 2003, 9(5):1045–1050.PubMed

47.

Akerman S, Holland PR, Lasalandra MP, Goadsby PJ: Endocannabinoids in the Brainstem Modulate Dural Trigeminovascular Nociceptive Traffic via CB1 and “Triptan” Receptors: Implications in Migraine. Neuroscience 2013, 33: 14869–14877. 10.1523/JNEUROSCI.0943-13.2013PubMedCentralCrossRefPubMed

48.

Ramachandran R, Bhatt DK, Ploug KB, Hay-Schmidt A, Jansen-Olesen I, Gupta S, Olesen J: Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia 2014, 34(2):136–147. 10.1177/0333102413502735CrossRefPubMed

49.

Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA: Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001, 124(Pt 12):2490–2502.CrossRefPubMed

50.

Tassorelli C, Joseph SA, Buzzi MG, Nappi G: The effects on the central nervous system of nitroglycerin–putative mechanisms and mediators. Prog Neurobiol 1999, 57(6):607–624. 10.1016/S0301-0082(98)00071-9CrossRefPubMed

51.

Buzzi MG, Tassorelli C: Experimental models of migraine. Handb Clin Neurol 2010, 97: 109–123.CrossRefPubMed

52.

Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ: Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 2004, 47: 345–358.CrossRefPubMed

53.

Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J: Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 2005, 135: 235–245. 10.1016/j.neuroscience.2005.06.009CrossRefPubMed

54.

DeLeo JA, Yezierski RP: The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 2001, 90: 1–6. 10.1016/S0304-3959(00)00490-5CrossRefPubMed

55.

Galeotti N, Ghelardini C: St. John’s wort reversal of meningeal nociception: A natural therapeutic perspective for migraine pain. Phytomedicine 2013, 20(10):930–938. 10.1016/j.phymed.2013.03.007CrossRefPubMed

56.

Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A: N-(2-hydroxyethyl) hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol 1996, 300: 227–236. 10.1016/0014-2999(96)00015-5CrossRefPubMed

57.

Oddi S, Latini L, Viscomi MT, Bisicchia E, Molinari M, Maccarrone M: Distinct regulation of nNOS and iNOS by CB₂ receptor in remote delayed neurodegeneration. J Mol Med (Berl) 2012, 90(4):371–387. 10.1007/s00109-011-0846-zCrossRef

58.

Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Bátkai S, Gao B, Haskó G, Pacher P: Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 2010, 48(3):457–467. 10.1016/j.freeradbiomed.2009.11.022PubMedCentralCrossRefPubMed

59.

Colucci M, Maione F, Bonito MC, Piscopo A, Di Giannuario A, Pieretti S: New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation. Pharmacol Res 2008, 57(6):419–425. 10.1016/j.phrs.2008.04.004CrossRefPubMed

Title: Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model
Authors: Rosaria Greco
Antonina Stefania Mangione
Giorgio Sandrini
Giuseppe Nappi
Cristina Tassorelli
Publication date: 01-12-2014
Publisher: Springer Milan
Published in: The Journal of Headache and Pain / Issue 1/2014
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/1129-2377-15-14

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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