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. 2010 Apr;7(2):191–196. doi: 10.1016/j.nurt.2010.02.003

The PACAP receptor: A novel target for migraine treatment

Henrik W Schytz 1, Jes Olesen 1, Messoud Ashina 1,
PMCID: PMC5084100  PMID: 20430318

Summary

The origin of migraine pain has not yet been clarified, but accumulating data point to neuropeptides present in the perivascular space of cranial vessels as important mediators of nociceptive input during migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in sensory trigeminal neurons and may modulate nociception at different levels of the nervous system. Human experimental studies have shown that PACAP-38 infusion induces marked dilatation of extracerebral vessels and delayed migraine-like attacks in migraine patients. PACAP selectively activates the PAC1 receptor, which suggests a possible signaling pathway implicated in migraine pain. This review summarizes the current evidence supporting the involvement of PACAP in migraine pathophysiology and the PAC1 receptor as a possible novel target for migraine treatment.

Key Words: Migraine, vasodilatation, mast-cell degranulation, trigeminal nociceptive system, human experimental headache models, drug targets

References

  • 1.Andlin-Sobocki P, Jönsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol. 2005;12(Suppl 1):1–27. doi: 10.1111/j.1468-1331.2005.01202.x. [DOI] [PubMed] [Google Scholar]
  • 2.Olesen J, Tfelt-Hansen P, Ashina M. Finding New drug targets for the treatment of migraine attacks. Cephalalgia. 2009;29:909–920. doi: 10.1111/j.1468-2982.2008.01837.x. [DOI] [PubMed] [Google Scholar]
  • 3.Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 2009;8:679–690. doi: 10.1016/S1474-4422(09)70090-0. [DOI] [PubMed] [Google Scholar]
  • 4.Uddman R, Tajti J, MÖller S, Sundler F, Edvinsson L. Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res. 1999;826:193–199. doi: 10.1016/S0006-8993(99)01260-3. [DOI] [PubMed] [Google Scholar]
  • 5.Edvinsson L, Elsås T, Suzuki N, Shimizu T, Lee TJ. Origin and co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat. Microsc Res Tech. 2001;53:221–228. doi: 10.1002/jemt.1086. [DOI] [PubMed] [Google Scholar]
  • 6.Nozaki K, Moskowitz MA, Maynard KI, et al. Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab. 1993;13:70–79. doi: 10.1038/jcbfm.1993.9. [DOI] [PubMed] [Google Scholar]
  • 7.Suzuki N, Hardebo JE. Anatomical basis for a parasympathetic and sensory innervation of the intracranial segment of the internal carotid artery in man: possible implication for vascular headache. J Neurol Sci. 1991;104:19–31. doi: 10.1016/0022-510X(91)90211-O. [DOI] [PubMed] [Google Scholar]
  • 8.Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61. doi: 10.1046/j.1468-2982.2002.00310.x. [DOI] [PubMed] [Google Scholar]
  • 9.Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor triggers genuine migraine attacks. Eur J Neurol. 1994;1:73–80. doi: 10.1111/j.1468-1331.1994.tb00053.x. [DOI] [PubMed] [Google Scholar]
  • 10.Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25. doi: 10.1093/brain/awn307. [DOI] [PubMed] [Google Scholar]
  • 11.Miyata A, Arimura A, Dahl RR, et al. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun. 1989;164:567–574. doi: 10.1016/0006-291X(89)91757-9. [DOI] [PubMed] [Google Scholar]
  • 12.Vaudry D, Falluel-Morel A, Bourgault S, et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 2009;61:283–357. doi: 10.1124/pr.109.001370. [DOI] [PubMed] [Google Scholar]
  • 13.Arimura A, Somogyvári-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C. Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology. 1991;129:2787–2789. doi: 10.1210/endo-129-5-2787. [DOI] [PubMed] [Google Scholar]
  • 14.Ghatei MA, Takahashi K, Suzuki Y, Gardiner J, Jones PM, Bloom SR. Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues. J Endocrinol. 1993;136:159–166. doi: 10.1677/joe.0.1360159. [DOI] [PubMed] [Google Scholar]
  • 15.Hannibal J, Mikkelsen JD, Clausen H, Holst JJ, Wulff BS, Fahrenkrug J. Gene expression of pituitary adenylate cyclase activating polypeptide (PACAP) in the rat hypothalamus. Regul Pept. 1995;55:133–148. doi: 10.1016/0167-0115(94)00099-J. [DOI] [PubMed] [Google Scholar]
  • 16.Mikkelsen JD, Hannibal J, Fahrenkrug J, Larsen PJ, Olcese J, McArdle C. Pituitary adenylate cyclase activating peptide-38 (PACAP-38), PACAP-27, and PACAP related peptide (PRP) in the rat median eminence and pituitary. J Neuroendocrinol. 1995;7:47–55. doi: 10.1111/j.1365-2826.1995.tb00666.x. [DOI] [PubMed] [Google Scholar]
  • 17.Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76:176–183. doi: 10.1016/S0165-1838(99)00024-7. [DOI] [PubMed] [Google Scholar]
  • 18.Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L. Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord Cl and C2. Cephalalgia. 2002;22:112–116. doi: 10.1046/j.1468-2982.2002.00324.x. [DOI] [PubMed] [Google Scholar]
  • 19.Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev. 2000;52:269–324. [PubMed] [Google Scholar]
  • 20.Mulder H, Uddman R, Moller K, et al. Pituitary adenylate cyclase activating polypeptide is expressed in autonomic neurons. Regul Pept. 1995;59:121–128. doi: 10.1016/0167-0115(95)00082-M. [DOI] [PubMed] [Google Scholar]
  • 21.Harmar AJ, Arimura A, Gozes I, et al. International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev. 1998;50:265–270. [PMC free article] [PubMed] [Google Scholar]
  • 22.Dickson L, Finlayson K. VPAC and PAC receptors: from ligands to function. Pharmacol Ther. 2009;121:294–316. doi: 10.1016/j.pharmthera.2008.11.006. [DOI] [PubMed] [Google Scholar]
  • 23.Dickinson T, Fleetwood-Walker SM. VIP and PACAP: very important in pain? Trends Pharmacol Sci. 1999;20:324–329. doi: 10.1016/S0165-6147(99)01340-1. [DOI] [PubMed] [Google Scholar]
  • 24.Knutsson M, Edvinsson L. Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. Neuroreport. 2002;13:507–509. doi: 10.1097/00001756-200203250-00030. [DOI] [PubMed] [Google Scholar]
  • 25.Zagami AS, Edvinsson L, HK L., Goadsby PJ. Stimulation of the superior sagittal sinus causes extracranial release of PACAP. Cephalalgia. 1995;15(Suppl 14):109–109. [Google Scholar]
  • 26.Yamitsky D, Goor-Aryeh I, Bajwa ZH, et al. Wolff Award: Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache. 2003;43:704–714. doi: 10.1046/j.1526-4610.2003.03127.x. [DOI] [PubMed] [Google Scholar]
  • 27.Maizels M, Scott B, Cohen W, Chen W. Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial. JAMA. 1996;276:319–321. doi: 10.1001/jama.276.4.319. [DOI] [PubMed] [Google Scholar]
  • 28.Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, Pang X, Theoharides TC. Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res. 1999;849:1–15. doi: 10.1016/S0006-8993(99)01855-7. [DOI] [PubMed] [Google Scholar]
  • 29.Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P. Arterial responses during migraine headache. Lancet. 1990;336:837–839. doi: 10.1016/0140-6736(90)92339-J. [DOI] [PubMed] [Google Scholar]
  • 30.Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet. 1991;338:13–17. doi: 10.1016/0140-6736(91)90005-A. [DOI] [PubMed] [Google Scholar]
  • 31.Uddman R, Goadsby PJ, Jansen I, Edvinsson L. PACAP, a VIP-like peptide: immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J Cereb Blood Flow Metab. 1993;13:291–297. doi: 10.1038/jcbfm.1993.36. [DOI] [PubMed] [Google Scholar]
  • 32.Seki Y, Suzuki Y, Baskaya MK, et al. The effects of pituitary adenylate cyclase-activating polypeptide on cerebral arteries and vertebral artery blood flow in anesthetized dogs. Eur J Pharmacol. 1995;275:259–266. doi: 10.1016/0014-2999(95)00011-9. [DOI] [PubMed] [Google Scholar]
  • 33.Boni LJ, Ploug KB, Olesen J, Jansen-Olesen I, Gupta S. The in vivo effect of VIP, PACAP-38 and PACAP-27 and mRNA expression of their receptors in rat middle meningeal artery. Cephalalgia. 2009;29:837–847. doi: 10.1111/j.1468-2982.2008.01807.x. [DOI] [PubMed] [Google Scholar]
  • 34.Birk S, Sitarz JT, Petersen KA, et al. The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers. Regul Pept. 2007;140:185–191. doi: 10.1016/j.regpep.2006.12.010. [DOI] [PubMed] [Google Scholar]
  • 35.Baun M, Olesen J, Jansen-Olesen I. Expression studies and pharmacological characterization of VIP and PACAP receptors in the cerebral circulation of the rat. Cephalalgia. 2009;29(Suppl 1):133–133. [Google Scholar]
  • 36.Baun M, Chan KY, Olesen J, Jansen-Olesen I, Gupta S, Maassen Van Den Brink A. Pharmacological characterization and mRNA expression studies of VIP and PACAP receptors in human coronary arteries. Cephalalgia. 2009;29(Suppl 1):132–132. [Google Scholar]
  • 37.Levy D. Migraine pain, meningeal inflammation, and mast cells. Curr Pain Headache Rep. 2009;13:237–240. doi: 10.1007/s11916-009-0040-y. [DOI] [PubMed] [Google Scholar]
  • 38.Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev. 2005;49:65–76. doi: 10.1016/j.brainresrev.2004.11.006. [DOI] [PubMed] [Google Scholar]
  • 39.Heatley RV, Denburg JA, Bayer N, Bienenstock J. Increased plasma histamine levels in migraine patients. Clin Allergy. 1982;12:145–149. doi: 10.1111/j.1365-2222.1982.tb01633.x. [DOI] [PubMed] [Google Scholar]
  • 40.Lassen LH, Thomsen LL, Olesen J. Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine. Neuroreport. 1995;6:1475–1479. doi: 10.1097/00001756-199507310-00003. [DOI] [PubMed] [Google Scholar]
  • 41.Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain. 2007;130:166–176. doi: 10.1016/j.pain.2007.03.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Zhang XC, Strassman AM, Burstein R, Levy D. Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther. 2007;322:806–812. doi: 10.1124/jpet.107.123745. [DOI] [PubMed] [Google Scholar]
  • 43.Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123:398–410. doi: 10.1111/j.1365-2567.2007.02705.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Odum L, Petersen LJ, Skov PS, Ebskov LB. Pituitary adenylate cyclase activating polypeptide (PACAP) is localized in human dermal neurons and causes histamine release from skin mast cells. Inflamm Res. 1998;47:488–492. doi: 10.1007/s000110050363. [DOI] [PubMed] [Google Scholar]
  • 45.Ottosson A, Edvinsson L. Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia. 1997;17:166–174. doi: 10.1046/j.1468-2982.1997.1703166.x. [DOI] [PubMed] [Google Scholar]
  • 46.Dickson L, Aramori I, McCulloch J, Sharkey J, Finlayson K. A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology. Neuropharmacology. 2006;51:1086–1098. doi: 10.1016/j.neuropharm.2006.07.017. [DOI] [PubMed] [Google Scholar]
  • 47.Levy D, Strassman AM. Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors. J Physiol. 2002;538:483–493. doi: 10.1113/jphysiol.2001.013175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Ingram SL, Williams JT. Modulation of the hyperpolarization-activated current (Ih) by cyclic nucleotides in guinea-pig primary afferent neurons. J Physiol. 1996;492:97–106. doi: 10.1113/jphysiol.1996.sp021292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Akerman S, Goadsby PJ. VPAC1 and PAC1 receptor antagonists inhibit activation of the parasympathetic outflow to the cranial vasculature to prevent autonomic responses and neuronal firing in the trigeminocervical complex. Cephalalgia. 2009;29(Suppl 1):130–130. [Google Scholar]
  • 50.Tajti J, Uddman R, Edvinsson L. Neuropeptide localization in the “migraine generator” region of the human brainstem. Cephalalgia. 2001;21:96–101. doi: 10.1046/j.1468-2982.2001.00140.x. [DOI] [PubMed] [Google Scholar]
  • 51.Basbaum AI, Clanton CH, Fields HL. Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic study of pain modulating systems. J Comp Neurol. 1978;178:209–224. doi: 10.1002/cne.901780203. [DOI] [PubMed] [Google Scholar]
  • 52.Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658–660. doi: 10.1038/nm0795-658. [DOI] [PubMed] [Google Scholar]
  • 53.Hashimoto H, Shintani N, Baba A. New insights into the central PACAPergic system from the phenotypes in PACAP- and PACAP receptor-knockout mice. Ann NY Acad Sci. 2006;1070:75–89. doi: 10.1196/annals.1317.038. [DOI] [PubMed] [Google Scholar]
  • 54.Zhang Y, Malmberg AB, Yaksh TL, Sjölund B, Sundler F, Håkanson R. Capsaicin-evoked release of pituitary adenylate cyclase activating peptide (PACAP) and calcitonin gene-related peptide (CGRP) from rat spinal cord in vivo. Regul Pept. 1997;69:83–87. doi: 10.1016/S0167-0115(97)02133-2. [DOI] [PubMed] [Google Scholar]
  • 55.Mabuchi T, Shintani N, Matsumura S, et al. Pituitary adenylate cyclase-activating polypeptide is required for the development of spinal sensitization and induction of neuropathic pain. J Neurosci. 2004;24:7283–7291. doi: 10.1523/JNEUROSCI.0983-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705. doi: 10.1016/j.tins.2003.09.017. [DOI] [PubMed] [Google Scholar]
  • 57.Jongsma H, Pettersson LM, Zhang YZ, et al. Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor. Neuroreport. 2001;12:2215–2219. doi: 10.1097/00001756-200107200-00034. [DOI] [PubMed] [Google Scholar]
  • 58.Davis-Taber R, Baker S, Lehto SG, et al. Central pituitary adenylate cyclase 1 receptors modulate nociceptive behaviors in both inflammatory and neuropathic pain states. J Pain. 2008;9:449–456. doi: 10.1016/j.jpain.2008.01.329. [DOI] [PubMed] [Google Scholar]
  • 59.Ohsawa M, Brailoiu GC, Shiraki M, Dun NJ, Paul K, Tseng LF. Modulation of nociceptive transmission by pituitary adenylate cyclase activating polypeptide in the spinal cord of the mouse. Pain. 2002;100:27–34. doi: 10.1016/S0304-3959(02)00207-5. [DOI] [PubMed] [Google Scholar]
  • 60.Hansen JM, Sitarz J, Birk S, et al. Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia. 2006;26:992–1003. doi: 10.1111/j.1468-2982.2006.01149.x. [DOI] [PubMed] [Google Scholar]
  • 61.Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28:226–236. doi: 10.1111/j.1468-2982.2007.01497.x. [DOI] [PubMed] [Google Scholar]
  • 62.Schytz HW, Holst H, Arendt-Nielsen L, Olesen L, Ashina M. Cutaneous nociception and neurogenic inflammation evoked by VIP and PACAP38: a human experimental study. Cephalalgia. 2009;29(12):1358–1358. [Google Scholar]
  • 63.Banks WA, Kastin AJ, Komaki G, Arimura A. Passage of pituitary adenylate cyclase activating polypeptide 1–27 and pituitary adenylate cyclase activating polypeptidel-38 across the blood-brain barrier. J Pharmacol Exp Ther. 1993;267:690–696. [PubMed] [Google Scholar]
  • 64.Birk S, Kruuse C, Petersen KA, Tfelt-Hansen P, Olesen J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia. 2006;26:1304–1309. doi: 10.1111/j.1468-2982.2006.01218.x. [DOI] [PubMed] [Google Scholar]
  • 65.Edvinsson L, Nilsson E, Jansen-Olesen I. Inhibitory effect of BIBN4096BS, CGRP{8–37}, a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br J Pharmacol. 2007;150:633–640. doi: 10.1038/sj.bjp.0707134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Ho TW, Mannix LK, Fan X, MK-0974 Protocol 004 Study Group et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304–1312. doi: 10.1212/01.WNL.0000286940.29755.61. [DOI] [PubMed] [Google Scholar]

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