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Open Access 01-12-2018 | Review article

PACAP and its role in primary headaches

Authors: Lars Edvinsson, János Tajti, Levente Szalárdy, László Vécsei

Published in: The Journal of Headache and Pain | Issue 1/2018

Abstract

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC₁, VPAC₁, and VPAC₂) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics.

Schulte LH, May A (2016) The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139:1987–1993CrossRefPubMed

Arimura A (2007) PACAP: the road to discovery. Peptides 28:1617–1619CrossRefPubMed

Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357CrossRefPubMed

Alexandre D, Anouar Y, Jegou S, Fournier A, Vaudry H (1999) A cloned frog vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide receptor exhibits pharmacological and tissue distribution characteristics of both VPAC1 and VPAC2 receptors in mammals. Endocrinology 140:1285–1293CrossRefPubMed

Wong AO, Leung MY, Shea WL, Tse LY, Chang JP, Chow BK (1998) Hypophysiotropic action of pituitary adenylate cyclase-activating polypeptide (PACAP) in the goldfish: immunohistochemical demonstration of PACAP in the pituitary, PACAP stimulation of growth hormone release from pituitary cells, and molecular cloning of pituitary type I PACAP receptor. Endocrinology 139:3465–3479CrossRefPubMed

Nowak JZ, Zawilska JB (2003) PACAP in avians: origin, occurrence, and receptors--pharmacological and functional considerations. Curr Pharm Des 9:467–481CrossRefPubMed

Mutt V, Said SI (1974) Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination. Eur J Biochem 42:581–589CrossRefPubMed

Bataille D, Gespach C, Laburthe M, Amiranoff B, Tatemoto K, Vauclin N, Mutt V, Rosselin G (1980) Porcine peptide having N-terminal histidine and C-terminal isoleucine amide (PHI): vasoactive intestinal peptide (VIP) and secretin-like effects in different tissues from the rat. FEBS Lett 114:240–242CrossRefPubMed

Zhou ZC, Gardner JD, Jensen RT (1989) Interaction of peptides related to VIP and secretin with Guinea pig pancreatic acini. Am J Phys 256:G283–G290

10.

Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574CrossRefPubMed

11.

Uddman R, Malm L, Sundler F (1980) The origin of vasoactive intestinal polypeptide (VIP) nerves in the feline nasal mucosa. Acta Otolaryngol 89:152–156CrossRefPubMed

12.

Grunditz T, Hakanson R, Hedge G, Rerup C, Sundler F, Uddman R (1986) Peptide histidine isoleucine amide stimulates thyroid hormone secretion and coexists with vasoactive intestinal polypeptide in intrathyroid nerve fibers from laryngeal ganglia. Endocrinology 118:783–790CrossRefPubMed

13.

Laburthe M, Couvineau A, Tan V (2007) Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides 28:1631–1639CrossRefPubMed

14.

Schytz HW, Olesen J, Ashina M (2010) The PACAP receptor: a novel target for migraine treatment. Neurotherapeutics 7:191–196CrossRefPubMedPubMedCentral

15.

Jansen-Olesen I, Baun M, Amrutkar DV, Ramachandran R, Christophersen DV, Olesen J (2014) PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides 48:53–64CrossRefPubMed

16.

Palkovits M, Somogyvari-Vigh A, Arimura A (1995) Concentrations of pituitary adenylate cyclase activating polypeptide (PACAP) in human brain nuclei. Brain Res 699:116–120CrossRefPubMed

17.

Masuo Y, Ohtaki T, Masuda Y, Tsuda M, Fujino M (1992) Binding sites for pituitary adenylate cyclase activating polypeptide (PACAP): comparison with vasoactive intestinal polypeptide (VIP) binding site localization in rat brain sections. Brain Res 575:113–123CrossRefPubMed

18.

Fahrenkrug J, Hannibal J (2011) Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands. Gen Comp Endocrinol 171:105–113CrossRefPubMed

19.

Koves K, Kantor O, Scammell JG, Arimura A (1998) PACAP colocalizes with luteinizing and follicle-stimulating hormone immunoreactivities in the anterior lobe of the pituitary gland. Peptides 19:1069–1072CrossRefPubMed

20.

Borzsei R, Mark L, Tamas A, Bagoly T, Bay C, Csanaky K, Banki E, Kiss P, Vaczy A, Horvath G, Nemeth J, Szauer E, Helyes Z, Reglodi D (2009) Presence of pituitary adenylate cyclase activating polypeptide-38 in human plasma and milk. Eur J Endocrinol 160:561–565CrossRefPubMed

21.

Moody TW, Ito T, Osefo N, Jensen RT (2011) VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes 18:61–67CrossRefPubMedPubMedCentral

22.

Barberi M, Muciaccia B, Morelli MB, Stefanini M, Cecconi S, Canipari R (2007) Expression localisation and functional activity of pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide and their receptors in mouse ovary. Reproduction 134:281–292CrossRefPubMed

23.

Masuo Y, Tokito F, Matsumoto Y, Shimamoto N, Fujino M (1994) Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) and its binding sites in the rat brain. Neurosci Lett 170:43–46CrossRefPubMed

24.

Koves K, Arimura A, Somogyvari-Vigh A, Vigh S, Miller J (1990) Immunohistochemical demonstration of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, in the ovine hypothalamus. Endocrinology 127:264–271CrossRefPubMed

25.

Hashimoto H, Shintani N, Tanida M, Hayata A, Hashimoto R, Baba A (2011) PACAP is implicated in the stress axes. Curr Pharm Des 17:985–989CrossRefPubMedPubMedCentral

26.

Reglodi D, Kiss P, Lubics A, Tamas A (2011) Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr Pharm Des 17:962–972CrossRefPubMed

27.

Seaborn T, Masmoudi-Kouli O, Fournier A, Vaudry H, Vaudry D (2011) Protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against apoptosis. Curr Pharm Des 17:204–214CrossRefPubMed

28.

Ohtsuka M, Fukumitsu H, Furukawa S (2008) PACAP decides neuronal laminar fate via PKA signaling in the developing cerebral cortex. Biochem Biophys Res Commun 369:1144–1149CrossRefPubMed

29.

Watanabe J, Nakamachi T, Matsuno R, Hayashi D, Nakamura M, Kikuyama S, Nakajo S, Shioda S (2007) Localization, characterization and function of pituitary adenylate cyclase-activating polypeptide during brain development. Peptides 28:1713–1719CrossRefPubMed

30.

Reglodi D, Kiss P, Horvath G, Lubics A, Laszlo E, Tamas A, Racz B, Szakaly P (2012) Effects of pituitary adenylate cyclase activating polypeptide in the urinary system, with special emphasis on its protective effects in the kidney. Neuropeptides 46:61–70CrossRefPubMed

31.

Ferencz A, Weber G, Helyes Z, Hashimoto H, Baba A, Reglodi D (2010) Presence of endogenous PACAP-38 ameliorated intestinal cold preservation tissue injury. J Mol Neurosci 42:428–434CrossRefPubMed

32.

Racz B, Reglodi D, Horvath G, Szigeti A, Balatonyi B, Roth E, Weber G, Alotti N, Toth G, Gasz B (2010) Protective effect of PACAP against doxorubicin-induced cell death in cardiomyocyte culture. J Mol Neurosci 42:419–427CrossRefPubMed

33.

Elekes K, Sandor K, Moricz A, Kereskai L, Kemeny A, Szoke E, Perkecz A, Reglodi D, Hashimoto H, Pinter E, Szolcsanyi J, Helyes Z (2011) Pituitary adenylate cyclase-activating polypeptide plays an anti-inflammatory role in endotoxin-induced airway inflammation: in vivo study with gene-deleted mice. Peptides 32:1439–1446CrossRefPubMed

34.

Zhou CJ, Shioda S, Yada T, Inagaki N, Pleasure SJ, Kikuyama S (2002) PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways. Curr Protein Pept Sci 3:423–439CrossRefPubMed

35.

Warren JB, Cockcroft JR, Larkin SW, Kajekar R, Macrae A, Ghatei MA, Bloom SR (1992) Pituitary adenylate cyclase activating polypeptide is a potent vasodilator in humans. J Cardiovasc Pharmacol 20:83–87PubMed

36.

Ishizuka Y, Kashimoto K, Mochizuki T, Sato K, Ohshima K, Yanaihara N (1992) Cardiovascular and respiratory actions of pituitary adenylate cyclase-activating polypeptides. Regul Pept 40:29–39CrossRefPubMed

37.

Naruse S, Suzuki T, Ozaki T, Nokihara K (1993) Vasodilator effect of pituitary adenylate cyclase activating polypeptide (PACAP) on femoral blood flow in dogs. Peptides 14:505–510CrossRefPubMed

38.

Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14:1289–1303CrossRefPubMed

39.

Moller K, Zhang YZ, Hakanson R, Luts A, Sjolund B, Uddman R, Sundler F (1993) Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: immunocytochemical and immunochemical evidence. Neuroscience 57:725–732CrossRefPubMed

40.

Baeres FM, Moller M (2004) Origin of PACAP-immunoreactive nerve fibers innervating the subarachnoidal blood vessels of the rat brain. J Cereb Blood Flow Metab 24:628–635CrossRefPubMed

41.

Nielsen HS, Hannibal J, Fahrenkrug J (1998) Embryonic expression of pituitary adenylate cyclase-activating polypeptide in sensory and autonomic ganglia and in spinal cord of the rat. J Comp Neurol 394:403–415CrossRefPubMed

42.

Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L (1999) Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 76:176–183CrossRefPubMed

43.

Hou M, Uddman R, Tajti J, Edvinsson L (2003) Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. Brain Res 964:179–186CrossRefPubMed

44.

Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L (2015) Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res 1600:93–109CrossRefPubMed

45.

Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L (2002) Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 22:112–116CrossRefPubMed

46.

Tajti J, Uddman R, Edvinsson L (2001) Neuropeptide localization in the "migraine generator" region of the human brainstem. Cephalalgia 21:96–101CrossRefPubMed

47.

Legradi G, Shioda S, Arimura A (1994) Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity in autonomic regulatory areas of the rat medulla oblongata. Neurosci Lett 176:193–196CrossRefPubMed

48.

Uddman R, Tajti J, Moller S, Sundler F, Edvinsson L (1999) Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res 826:193–199CrossRefPubMed

49.

Csati A, Tajti J, Kuris A, Tuka B, Edvinsson L, Warfvinge K (2012) Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion. Neuroscience 202:158–168CrossRefPubMed

50.

Steinberg A, Frederiksen SD, Blixt FW, Warfvinge K, Edvinsson L (2016) Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets. J Headache Pain 17:78CrossRefPubMedPubMedCentral

51.

Mulder H, Uddman R, Moller K, Zhang YZ, Ekblad E, Alumets J, Sundler F (1994) Pituitary adenylate cyclase activating polypeptide expression in sensory neurons. Neuroscience 63:307–312CrossRefPubMed

52.

Edvinsson L, Uddman R (2005) Neurobiology in primary headaches. Brain Res Brain Res Rev 48:438–456CrossRefPubMed

53.

Cauvin A, Robberecht P, De Neef P, Gourlet P, Vandermeers A, Vandermeers-Piret MC, Christophe J (1991) Properties and distribution of receptors for pituitary adenylate cyclase activating peptide (PACAP) in rat brain and spinal cord. Regul Pept 35:161–173CrossRefPubMed

54.

Suda K, Smith DM, Ghatei MA, Murphy JK, Bloom SR (1991) Investigation and characterization of receptors for pituitary adenylate cyclase-activating polypeptide in human brain by radioligand binding and chemical cross-linking. J Clin Endocrinol Metab 72:958–964CrossRefPubMed

55.

Chaudhary P, Baumann TK (2002) Expression of VPAC2 receptor and PAC1 receptor splice variants in the trigeminal ganglion of the adult rat. Brain Res Mol Brain Res 104:137–142CrossRefPubMed

56.

Saghy E, Payrits M, Helyes Z, Reglodi D, Banki E, Toth G, Couvineau A, Szoke E (2015) Stimulatory effect of pituitary adenylate cyclase-activating polypeptide 6-38, M65 and vasoactive intestinal polypeptide 6-28 on trigeminal sensory neurons. Neuroscience 308:144–156CrossRefPubMed

57.

Knutsson M, Edvinsson L (2002) Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. Neuroreport 13:507–509CrossRefPubMed

58.

Goadsby PJ, Edvinsson L (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117(Pt 3):427–434CrossRefPubMed

59.

Goadsby PJ, Edvinsson L (1994) Joint 1994 Wolff award presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache 34:394–399CrossRefPubMed

60.

Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132:16–25CrossRefPubMed

61.

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

62.

Sicuteri F, Del Bene E, Poggioni M, Bonazzi A (1987) Unmasking latent dysnociception in healthy subjects. Headache 27:180–185CrossRefPubMed

63.

Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61CrossRefPubMed

64.

Amin FM, Asghar MS, Guo S, Hougaard A, Hansen AE, Schytz HW, van der Geest RJ, de Koning PJ, Larsson HB, Olesen J, Ashina M (2012) Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia 32:140–149CrossRefPubMed

65.

Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M (2014) Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 137:779–794CrossRefPubMed

66.

Amin FM, Hougaard A, Magon S, Asghar MS, Ahmad NN, Rostrup E, Sprenger T, Ashina M (2016) Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology 86:180–187CrossRefPubMed

67.

Guo S, Vollesen AL, Hansen YB, Frandsen E, Andersen MR, Amin FM, Fahrenkrug J, Olesen J, Ashina M (2016) Part II: biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia

68.

Guo S, Vollesen AL, Hansen RD, Esserlind AL, Amin FM, Christensen AF, Olesen J, Ashina M (2016) Part I: pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia

69.

Zhang YZ, Sjolund B, Moller K, Hakanson R, Sundler F (1993) Pituitary adenylate cyclase activating peptide produces a marked and long-lasting depression of a C-fibre-evoked flexion reflex. Neuroscience 57:733–737CrossRefPubMed

70.

Narita M, Dun SL, Dun NJ, Tseng LF (1996) Hyperalgesia induced by pituitary adenylate cyclase-activating polypeptide in the mouse spinal cord. Eur J Pharmacol 311:121–126CrossRefPubMed

71.

Davis-Taber R, Baker S, Lehto SG, Zhong C, Surowy CS, Faltynek CR, Scott VE, Honore P (2008) Central pituitary adenylate cyclase 1 receptors modulate nociceptive behaviors in both inflammatory and neuropathic pain states. J Pain 9:449–456CrossRefPubMed

72.

Jongsma H, Pettersson LM, Zhang Y, Reimer MK, Kanje M, Waldenstrom A, Sundler F, Danielsen N (2001) Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor. Neuroreport 12:2215–2219CrossRefPubMed

73.

Mabuchi T, Shintani N, Matsumura S, Okuda-Ashitaka E, Hashimoto H, Muratani T, Minami T, Baba A, Ito S (2004) Pituitary adenylate cyclase-activating polypeptide is required for the development of spinal sensitization and induction of neuropathic pain. J Neurosci 24:7283–7291CrossRefPubMed

74.

Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, Szabadfi K, Tuka B, Tajti J, Szolcsanyi J, Pinter E, Hashimoto H, Kun J, Reglodi D, Helyes Z (2012) Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 45:633–644CrossRefPubMed

75.

Martin M, Otto C, Santamarta MT, Torrecilla M, Pineda J, Schutz G, Maldonado R (2003) Morphine withdrawal is modified in pituitary adenylate cyclase-activating polypeptide type I-receptor-deficient mice. Brain Res Mol Brain Res 110:109–118CrossRefPubMed

76.

Missig G, Roman CW, Vizzard MA, Braas KM, Hammack SE, May V (2014) Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: implication for the sensory and behavioral effects of pain. Neuropharmacology 86:38–48CrossRefPubMedPubMedCentral

77.

Akerman S, Goadsby PJ (2015) Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: relevance to migraine. Sci Transl Med 7:308ra157CrossRefPubMed

78.

Sandor K, Bolcskei K, McDougall JJ, Schuelert N, Reglodi D, Elekes K, Petho G, Pinter E, Szolcsanyi J, Helyes Z (2009) Divergent peripheral effects of pituitary adenylate cyclase-activating polypeptide-38 on nociception in rats and mice. Pain 141:143–150CrossRefPubMed

79.

Helyes Z, Pozsgai G, Borzsei R, Nemeth J, Bagoly T, Mark L, Pinter E, Toth G, Elekes K, Szolcsanyi J, Reglodi D (2007) Inhibitory effect of PACAP-38 on acute neurogenic and non-neurogenic inflammatory processes in the rat. Peptides 28:1847–1855CrossRefPubMed

80.

Nemeth J, Reglodi D, Pozsgai G, Szabo A, Elekes K, Pinter E, Szolcsanyi J, Helyes Z (2006) Effect of pituitary adenylate cyclase activating polypeptide-38 on sensory neuropeptide release and neurogenic inflammation in rats and mice. Neuroscience 143:223–230CrossRefPubMed

81.

Zhang Y, Malmberg AB, Sjolund B, Yaksh TL (1996) The effect of pituitary adenylate cyclase activating peptide (PACAP) on the nociceptive formalin test. Neurosci Lett 207:187–190CrossRefPubMed

82.

Baun M, Pedersen MH, Olesen J, Jansen-Olesen I (2012) Dural mast cell degranulation is a putative mechanism for headache induced by PACAP-38. Cephalalgia 32:337–345CrossRefPubMed

83.

Bhatt DK, Gupta S, Olesen J, Jansen-Olesen I (2014) PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: possible involvement of mast cells. Cephalalgia 34:877–886CrossRefPubMed

84.

Mori T, Kawashima T, Beppu Y, Takagi K (1994) Histamine release induced by pituitary adenylate cyclase activating polypeptide from rat peritoneal mast cells. Arzneimittelforschung 44:1044–1046PubMed

85.

Odum L, Petersen LJ, Skov PS, Ebskov LB (1998) Pituitary adenylate cyclase activating polypeptide (PACAP) is localized in human dermal neurons and causes histamine release from skin mast cells. Inflamm Res 47:488–492CrossRefPubMed

86.

Schytz HW (2010) Investigation of carbachol and PACAP38 in a human model of migraine. Dan Med Bull 57:B4223PubMed

87.

Zhang Y, Malmberg AB, Yaksh TL, Sjolund B, Sundler F, Hakanson R (1997) Capsaicin-evoked release of pituitary adenylate cyclase activating peptide (PACAP) and calcitonin gene-related peptide (CGRP) from rat spinal cord in vivo. Regul Pept 69:83–87CrossRefPubMed

88.

Tuka B, Helyes Z, Markovics A, Bagoly T, Nemeth J, Mark L, Brubel R, Reglodi D, Pardutz A, Szolcsanyi J, Vecsei L, Tajti J (2012) Peripheral and central alterations of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat in response to activation of the trigeminovascular system. Peptides 33:307–316CrossRefPubMed

89.

Zagami AS, Edvinsson L, Goadsby PJ (2014) Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol 1:1036–1040CrossRefPubMedPubMedCentral

90.

Zagami AS, Goadsby PJ, Edvinsson L (1990) Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 16:69–75CrossRefPubMed

91.

Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsanyi J, Szabo N, Toth E, Kincses ZT, Vecsei L, Tajti J (2013) Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia 33:1085–1095CrossRefPubMed

92.

Tuka B, Szabo N, Toth E, Kincses ZT, Pardutz A, Szok D, Kortesi T, Bagoly T, Helyes Z, Edvinsson L, Vecsei L, Tajti J (2016) Release of PACAP-38 in episodic cluster headache patients - an exploratory study. J Headache Pain 17:69CrossRefPubMedPubMedCentral

93.

Han X, Dong Z, Hou L, Wan D, Chen M, Tang W, Yu S (2015) Interictal plasma pituitary adenylate cyclase-activating polypeptide levels are decreased in migraineurs but remain unchanged in patients with tension-type headache. Clin Chim Acta 450:151–154CrossRefPubMed

94.

Zagami AS, Edvinsson L, Hoskin KL, Goadsby PJ (1995) Stimulation of the superior sagittal sinus causes extracranial release of PACAP. Cephalalgia 15(Suppl 14):109

95.

Reglodi D, Tamas A (2016) Pituitary Adenylate Cyclase activating polypeptide — PACAP. Cham. Springer International Publishing

96.

Erdling A, Sheykhzade M, Maddahi A, Bari F, Edvinsson L (2013) VIP/PACAP receptors in cerebral arteries of rat: characterization, localization and relation to intracellular calcium. Neuropeptides 47:85–92CrossRefPubMed

97.

Syed AU, Koide M, Braas KM, May V, Wellman GC (2012) Pituitary adenylate cyclase-activating polypeptide (PACAP) potently dilates middle meningeal arteries: implications for migraine. J Mol Neurosci 48:574–583CrossRefPubMedPubMedCentral

Title: PACAP and its role in primary headaches
Authors: Lars Edvinsson
János Tajti
Levente Szalárdy
László Vécsei
Publication date: 01-12-2018
Publisher: Springer Milan
Published in: The Journal of Headache and Pain / Issue 1/2018
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-018-0852-4

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PACAP and its role in primary headaches

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