Purinergic mechanisms in the nervous system: the role of adenosine triphosphate in the migraine pathophysiology

Year 2016, Volume: 5 Issue: 2, 132 - 152, 01.05.2016

Erkan Kılınç

https://doi.org/10.5505/abantmedj.2016.98250

Abstract

Notwithstanding that adenosine 5'-triphosphate ATP is an intracellular energy source, it is an important neurotransmitter and co-transmitter which play a role in purinergic signaling when it get out of the cell. Extracellular ATP is a signaling molecule in the most area of the body and it shows its effects via ionotropic P2X and metabotropic P2Y receptors in the central and peripheral nervous system. These purinergic receptors activated by ATP and other nucleotides demonstrate a wide distribution throughout the body. It is well established nowadays that ATP has function as a neurotransmitter in the central and peripheral nervous system and purinergic signaling plays a role in many physiological process and additionally in the pathological conditions such as pain, migraine and inflammation. Recently studies have showed that ATP has a role in initiation and propagation of somatic and visceral pains. ATP is able to initiate periferal pain signals via P2X3 and P2X2/3 receptors which are located primary afferent nerve terminals. When ATP activate these receptors, pain signals are produced by membrane depolarization via cation inflow to the cell. Transmission of pain signals from periferal to central are mediated by P2X2, P2X3 and P2X6 receptors which are located second order neurons. Although it has been known that main process in initiation of migraine pain is activation of the trigeminovascular system, pathophysiology of migraine is not yet completely understood. It has been claimed by studies recently that ATP may play a key role via its purinoceptors in migraine headache as well like somatic pains. In the present review, functions of extracellular ATP and its purinoceptors in the migraine pathophysiology and new treatment approaches were discussed.

Keywords

Adenosine triphosphate, pain, trigeminovascular system, migraine, purinergic receptors.

Sinir Sisteminde Pürinerjik Mekanizmalar: Adenozin Trifosfatın Migren Patofizyolojisindeki Rolü

Abstract

Adenozin 5'-trifosfat ATP hücre içi enerji kaynağı olmasının yanında hücre dışına çıktığında pürinerjik haberleşmede rol oynayan önemli bir nörotansmitter ve ko-transmitterdir. Vücudun birçok bölümünde bir sinyal molekülü olan ekstrasellüler ATP, merkezi ve periferik sinir sisteminde etkisini iyonotropik P2X ve metabotropik P2Y reseptörleri aracılığı ile gösterir. ATP ve diğer nükleotitlerin aktive ettiği bu pürinerjik reseptörler tüm vücut boyunca dağılım gösterir. ATP' nin merkezi ve periferik sinir sisteminde bir nörotransmitter olarak işlevinin olduğu ve pürinerjik haberleşmenin birçok fizyolojik olayda ve ayrıca ağrı, migren ve inflamasyon gibi patofizyolojik durumlarda rol oynadığı günümüzde daha iyi bilinmektedir. Son zamanlarda yapılan çalışmalar ATP' nin somatik ve viseral ağrıların başlatılmasında ve iletilmesinde rolü olduğunu göstermektedir. ATP primer afferent sinir terminallerinde bulunan P2X3 ve P2X2/3 reseptörleri aracılığı ile periferik ağrı sinyallerini başlatabilmektedir. ATP bu reseptörleri aktive ettiğinde hücre içine hızlı bir katyon girişi ile membran depolarize olmakta ve ağrı sinyalleri oluşmaktadır. Ağrı sinyallerinin periferden merkeze aktarılmasına ise ikinci sıra nöronlarında bulunan P2X2, P2X3 ve P2X6 reseptörleri aracılık etmektedir. Migren ağrısının başlamasındaki asıl olayın trigeminovasküler sistemin aktivasyonu olduğu bilinmesine rağmen migren patofizyolojisi henüz anlaşılamamıştır. Son zamanlarda yapılan çalışmalarla somatik ağrılarda olduğu gibi bir viseral ağrı olan migren baş ağrısında da ATP' nin pürinoseptörleri aracılığı ile önemli bir rol oynayabileceği ileri sürülmektedir. Sunulan derlemede bir nörotransmitter olarak ekstrasellüler ATP ve pürinoseptörlerinin migren patofizyolojisindeki işlevleri ve yeni tedavi yaklaşımları tartışılmıştır.

Keywords

Adenozin trifosfat, ağrı, trigeminovasküler sistem, migren, pürinerjik reseptörler.

References

• 1. Holton P. The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 1959;145:494-504.
• 2. Edwards FA, Gibb AJ, Colquhoun D. ATP receptor-mediated synaptic currents in the central nervous system. Nature 1992;359:144-47.
• 3. Silinsky EM, Gerzanich V, Vanner SM. ATP mediates excitatory synaptic transmission in mammalian neurones. Br J Pharmacol 1992;106:762-63.
• 4. Evans RJ, Derkach V, Surprenant A. ATP mediates fast synaptic transmission in mammalian neurons. Nature 1992;357:503-05.
• 5. Burnstock G.Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci 2006;27:166-76.
• 6. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: an overview. Trends Neurosci 2009; 32:19-29.
• 7. Bulanova E, Bulfone-Paus S. P2 receptor-mediated signaling in mast cell biology. Purinergic Signal 2010;6:3-17.
• 8. Ralevic V, Dunn WR. Purinergic transmission in blood vessels. Auton Neurosci 2015;191:48-66.
• 9. Pankratov Y, Lalo U, Verkhratsky A, North RA. Vesicular release of ATP at central synapses. Pflugers Arch. 2006;452:589-97.
• 10. Sawada K, Echigo N, Juge N, Miyaji T, Otsuka M, Omote H, Yamamoto A, Moriyama Y. Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci USA 2008;105:5683-86.
• 11. Zimmermann H. Ectonucleotidases in the nervous system. Novartis Found Symp 2006;276:113-28.
• 12. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: an overview. Trends Neurosci 2009; 32:19-29.
• 13. Cieślak M, Czarnecka J, Roszek K, Komoszyński M. The role of purinergic signaling in the etiology of migraine and novel antimigraine treatment. Purinergic Signal 2015;11:307-16.
• 14. Lewis CJ, Ennion SJ, Evans RJ. P2 purinoceptor-mediated control of rat cerebral(pial) microvasculature; contribution of P2X and P2Y receptors. J. Physiol 2000; 527: 315-24.
• 15. Arulkumaran N, Unwin RJ, Tam FWK. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs 2011; 20: 897- 915.
• 16. Burnstock G. Purinergic receptors and pain. Curr Pharm Des 2009;15:1717- 35.
• 17. Abbracchio MP, Burnstock G. Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Therap 1994; 64: 445-75.
• 18. Atkinson L, Batten TF, Deuchars J. P2X(2) receptor immunoreactivity in the dorsal vagal complex and area postrema of the rat. Neuroscience 2000;99:683-96.
• 19. Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, BuckleyNJ, Parson SH, Deuchars J.Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci 2001;21:7143-52.
• 20. Boehm S. ATP stimulates sympathetic transmitter release via presynaptic P2X purinoceptors. J Neurosci 1999;19:737-46.
• 21. Burnstock G, Knight GE. Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 2004;240:31-304.
• 22. Slater NM, Barden JA, Murphy CR. Distributional changes of purinergic receptor subtypes (P2X 1-7) in uterine epithelial cells during early pregnancy. Histochem J 2000:365-72.
• 23. Ishii K, Kaneda M, Li H, Rockland KS, Hashikawa T. Neuron-specific distribution of P2X7 purinergic receptors in the monkey retina. J Comp Neurol 2003;459:267-77.
• 24. Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 2007;87:659-97.
• 25. Burnstock G. Noradrenaline and ATP: cotransmitters and neuromodulators. J Physiol Pharmacol 1995; 46:365-84.
• 26. Burnstock G. Purinergic signalling in the lower urinary tract. Acta Physiol (Oxf). 2013;207:40-52.
• 27. Burnstock G. The journey to establish purinergic signalling in the gut. Neurogastroenterol Motil 2008;20:8-19.
• 28. Sperlagh B, Vizi ES, Wirkner K, Illes P. P2X7 receptors in the nervous system. Prog Neurobiol 2006;78:327-46.
• 29. Liang S, Xu C, Li G, Gao Y. P2X receptors and modulation of pain transmission: focus on effects of drugs and compounds used in traditional Chinese medicine. Neurochem Int 2010;57:705-12.
• 30. Burnstock G. Purine-mediated signaling in pain and visceral perception. Trends Pharmacol Sci 2001;22:182-88.
• 31. Hamilton SG, Warburton J, Bhattachrjee A, Ward J, McMahon SB. ATP in human skin elicits a dose-related pain response which is potentiated under conditions of hyperalgesia. Brain 2000;123:1238-46.
• 32. Stanfa LC, Kontinen VK, Dickenson AH. Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats. Br J Pharmacol 2000;129:351-59.
• 33. Burnstock G. Purinergic mechanisms and pain-an update. Eur J Pharmacol. 2013;716:24-40.
• 34. Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R. P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 1998;10:3470-78.
• 35. Sokolova E, Skorinkin A, Moiseev I, Agrachev A, Nistri A, Giniatullin R. Experimental and modeling studies of desensitization of P2X3 receptors. Mol Pharmacol 2006;70:373-82.
• 36. Fabbretti E. ATP P2X3 receptors and neuronal sensitization. Front Cell Neurosci 2013;7:236.
• 37. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 2000;407:1011-15.
• 38. Sessle BJ. Peripheral and central mechanisms of orofacial pain and their clinical correlates. Minerva Anestesiol 2005;71:117-36.
• 39. Andó RD, Méhész B, Gyires K, Illes P, Sperlágh B. A comparative analysis of the activity of ligands acting at P2X and P2Y receptor subtypes in models of neuropathic, acute and inflammatory pain. Br J Pharmacol 2010;159:1106-17.
• 40. Fields RD, Burnstock G. Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 2006;7:423-36.
• 41. Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, SubietaA, Van Biesen TCartmell J, Bianchi B, Niforatos W, Kage K, Yu H, Mikusa J,Wismer CT, Zhu CZ, Chu K, Lee CH, Stewart AO, Polakowski J, Cox BF, Kowaluk E,Williams M, Sullivan J, Faltynek C. A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. U.S.A. 2002;99:17179-84.
• 42. Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP,Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W,Marsh K, Sullivan JP, Faltynek CR, Jarvis MF.A-740003 [N-(1-{[(cyanoimino) (5- quinolinylamino)methyl]amino}-2,2- dimethylpropyl)-2-(3,4-dimethoxyphenyl) acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther 2006;319:1376-85.
• 43. Nelson DW, Gregg RJ, Kort ME, Perez-Medrano A, Voight EA, Wang Y, Grayson G,Namovic MT, Donnelly-Roberts DL, Niforatos W, Honore P, Jarvis MF, Faltynek CR,Carroll WA. Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists. J Med Chem 2006;49:3659-66.
• 44. McGaraughty S, Chu KL, Namovic MT, Donnelly-Roberts DL, Harris RR, Zhang XF,Shieh CC, Wismer CT, Zhu CZ, Gauvin DM, Fabiyi AC, Honore P, Gregg RJ, Kort ME, Nelson DW, Carroll WA, Marsh K, Faltynek CR, Jarvis MF. P2X7-related modulation of pathological nociception in rats. Neuroscience. 2007;146:1817-28.
• 45. Collo G, Neidhart S, Kawashima E, Kosco-VilboisM, North RA, Buell G.Tissue distribution of the P2X7 receptor. Neuropharmacology 1997;36:1277-83.
• 46. Lee HY, Bardini M, Burnstock G. Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J Urol 2000;163:2002-07.
• 47. Pannicke T, Fischer W, Biedermann B, Schädlich H, Grosche J, Faude F, Wiedemann P, Allgaier C, Illes P, Burnstock G, Reichenbach A. P2X7 receptors in Muller glial cells from the human retina. J Neurosci 2000;20:5965-72.
• 48. Gerevich Z, Müller C, Illes P. Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons. Eur J Pharmacol 2005;521:34-38.
• 49. Ceruti S, Fumagalli M, Villa G, Verderio C, Abbracchio M. Purinoceptormediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium 2008;43:576-90.
• 50. Cui Y, Kataoka Y, Watanabe Y. Role of cortical spreading depression in the pathophysiology of migraine. Neurosci Bull 2014;30:812-22.
• 51. Tajti J, Szok D, Majláth Z, Tuka B, Csáti A, Vécsei L. Migraine and neuropeptides. Neuropeptides 2015;52:19-30.
• 52. Lewis DW. Toward the definition of childhood migraine. Curr Opin Pediatr 2004;16:628-36.
• 53. Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 2007;130:166-76.
• 54. Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci 2006;27:86-90.
• 55. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and treatment. N Engl J Med 2002;346:257-70.
• 56. Pietrobon D. Migraine: new molecular mechanisms. Neuroscientist 2005;11:373-86.
• 57. Burnstock G, Ralevic V. Purinergic signaling and blood vessels in health and disease. Pharmacol Rev 2014;66:102-92.
• 58. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994;117:199- 210.
• 59. Hautaniemi T, Petrenko N, Skorinkin A, Giniatullin R. The inhibitory action of the antimigraine nonsteroidal anti-inflammatory drug naproxen on P2X3 receptor-mediated responses in rat trigeminal neurons. Neuroscience 2012;209:32-8.
• 60. Giniatullin R, Nistri A. Desensitization properties of P2X3 receptors shaping pain signaling. Front Cell Neurosci 2013;7:245.
• 61. Staikopoulos V, Sessle BJ, Furness JB, Jennings EA. Localization of P2X2 and P2X3 receptors in rat trigeminal ganglion neurons. Neuroscience 2007;144:208-16.
• 62. Zakharov A, Vitale C, Kilinc E, Koroleva K, Fayuk D, Shelukhina I, Naumenko N,Skorinkin A, Khazipov R, Giniatullin R.Hunting for origins of migraine pain: cluster analysis of spontaneous and capsaicin-induced firing in meningeal trigeminal nerve fibers. Front Cell Neurosci 2015;9:287.
• 63. Kılınç E, Koroleva K, Guerrero-Toro C, Töre F, Giniatullin R. The Role of Adenosine Triphosphate and its Receptors in Migraine Pathophysiology. Acta Physiol (Oxf) Turkish Society of Physiological Sciences 41st National Physiology Congress 2015;215:44-5.
• 64. Haanes KA, Edvinsson L. Expression and characterization of purinergic receptors in rat middle meningeal arterypotential role in migraine. PLoS One 2014;9:e108782.
• 65. Nishizaki T. ATP- and adenosinemediated signaling in the central nervous system: adenosine stimulates glutamate release from astrocytes via A2a adenosine receptors. J Pharmacol Sci 2004;94:100-2.
• 66. Kruuse C, Lassen LH, Iversen HK, Oestergaard S, Olesen J. Dipyridamole may induce migraine in patients with migraine without aura. Cephalalgia 2006;26:925-33.
• 67. Sakuma I, Akaishi Y, Fukao M, Makita Y, Makita MA, Kobayashi T, Matsuno K, Miyazaki T, Yasuda H. Dipyridamole potentiates the antiaggregating effect of endothelium-derived relaxing factor. Thromb Res Suppl 1990;12:87-90.
• 68. Guieu R, Devaux C, Henry H, Bechis G, Pouget J, Mallet D. Adenosine and migraine. Can J Neurol Sci 1998;25:55-8.
• 69. Sollevi A, Belfrage M, Lundeberg T, Segerdahl M, Hansson P. Systemic adenosine infusion: a new treatment modality to alleviate neuropathic pain. Pain 1995;61:155-8.
• 70. Gurden MF, Coates J, Ellis F, Evans B, Foster M, Hornby E, Kennedy I, MartinDP, Strong P, Vardey CJ.Functional characterization of three adenosine receptor types. Br J Pharmacol 1993;109:693-8.
• 71. Sheehan M,Wilson D, Cousins R, Giles H. Relative intrinsic efficacy of adenosine A1 receptor agonist measured using functional and radioligand binding assays. Br J Pharmacol 2000;131:34P.
• 72. Sjolund KF, Segerdahl M, Sollevi A. Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain. Anesthesia Analgesia 1999;88:605-10.
• 73. Sjolund KF, Sollevi A, Segerdahl M, Lundeberg T. Intrathecal adenosine analog administration reduces substance Pin cerebrospinal fluid along with behavioral effects thatsuggest antinociception in rats. Anesthesia Analgesia 1997;85:627-32.
• 74. Giffin NJ, Kowacs F, Libri V, Williams P, Goadsby PJ, Kaube H. Effect of theadenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 2003;23:287-92.