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

Open Access 01-12-2022 | Migraine | Research

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

Authors: Song Guo, Charlotte Ernstsen, Anders Hay-Schmidt, David Møbjerg Kristensen, Messoud Ashina, Jes Olesen, Sarah Louise Christensen

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

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Abstract

Background

Calcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50–60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan.

Methods

In vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan.

Results

We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity.

Conclusions

Based on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.
Literature
1.
Migraine AM (2020) Ropper AH, editor. N Engl J Med 383(19):1866–1876
2.
Charles A, Pozo-Rosich P (2019) Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 394:1765–74 (Lancet Publishing Group)PubMedCrossRef
3.
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M et al (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15(4):382–390PubMedCrossRef
4.
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS (2014) Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 13(9):885–892PubMedCrossRef
5.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener H-C et al (2015) Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 14(11):1091–1100PubMedCrossRef
6.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M et al (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13(11):1100–1107PubMedCrossRef
7.
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(Pt 1):16–25PubMedCrossRef
8.
9.
10.
Ernstsen C, Christensen SL, Rasmussen RH, Nielsen BS, Jansen-Olesen I, Olesen J et al (2022) The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target? Brain 145(7):2450–2460PubMedCrossRef
11.
Kuburas A, Mason BN, Hing B, Wattiez AS, Reis AS, Sowers LP et al (2021) PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP. J Neurosci 41(21):4697–4715PubMedPubMedCentralCrossRef
12.
Christensen SL, Petersen S, Kristensen DM, Olesen J, Munro G (2019) Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain. Cephalalgia 39(14):1827–1837PubMedCrossRef
13.
Christensen SL, Petersen S, Sørensen DB, Olesen J, Jansen-Olesen I (2018) Cilostazol induces C-fos expression in the trigeminal nucleus caudalis and behavioural changes suggestive of headache with the migraine-like feature photophobia in female rats. Cephalalgia 38(3):452–465PubMedCrossRef
14.
Christensen SL, Munro G, Petersen S, Shabir A, Jansen-Olesen I, Kristensen DM et al (2020) ATP sensitive potassium (KATP) channel inhibition: A promising new drug target for migraine. Cephalalgia 40(7):650–664PubMedCrossRef
15.
Moye LS, Tipton AF, Dripps I, Sheets Z, Crombie A, Violin JD et al (2019) Delta opioid receptor agonists are effective for multiple types of headache disorders. Neuropharmacology 1(148):77–86CrossRef
16.
Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K et al (2012) Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 45(1):633–644PubMedCrossRef
17.
Ernstsen C, Christensen SL, Olesen J, Kristensen DM (2021) No additive effect of combining sumatriptan and olcegepant in the GTN mouse model of migraine. Cephalalgia 41(3):329–339
18.
Christensen SL, Ernstsen C, Olesen J, Kristensen DM (2020) No central action of CGRP antagonising drugs in the GTN mouse model of migraine. Cephalalgia 40(9):924–934
19.
Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA (2016) The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia 36(11):1048–1056PubMedPubMedCentralCrossRef
20.
Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) Characterization of a novel model of chronic migraine. Pain 155(2):269–274PubMedCrossRef
21.
Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI et al (2010) Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30(2):170–178PubMedPubMedCentralCrossRef
22.
Christensen SL, Rasmussen RH, Ernstsen C, La Cour S, David A, Chaker J et al (2021) CGRP-dependent signalling pathways involved in mouse models of GTN- cilostazol- and levcromakalim-induced migraine. Cephalalgia 41(14):1413–1426PubMedCrossRef
23.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh T (1994) Quantitative assessment of tactile allodynia evoked by unilateral ligation of the fifth and sixth lumbar nerves in the rat. J Neurosci 53:55–63
24.
Christensen SL, Hansen RB, Storm MA, Olesen J, Hansen TF, Ossipov M, et al (2020) Von Frey testing revisited: Provision of an online algorithm for improved accuracy of 50% thresholds. Eur J Pain 24(4):783–790
25.
Loomis CM, Dutzar B, Ojala EW, Hendrix L, Karasek C, Scalley-Kim M et al (2019) Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase-Activating Peptide. J Pharmacol Exp Ther 369(1):26–36CrossRef
26.
27.
Potvin PJ, Schutz RW (2000) Statistical power for the two-factor repeated measures ANOVA. Behav Res Methods Instrum Comput 32(2):347–356PubMedCrossRef
28.
Olesen J, Jansen-Olesen I (2012) Towards a reliable animal model of migraine. Cephalalgia 32(7):578–580PubMedCrossRef
29.
Greco R, Demartini C, Zanaboni AM, Tassorelli C (2018) Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing. J Headache Pain 19(1):51PubMedPubMedCentralCrossRef
30.
Capuano A, Greco MC, Navarra P, Tringali G (2014) Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization. Eur J Pharmacol 740:97–102PubMedCrossRef
31.
Greco R, Mangione AS, Siani F, Blandini F, Vairetti M, Nappi G et al (2014) Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia. Cephalalgia 34(8):616–623CrossRef
32.
Anapindi KDB, Yang N, Romanova EV, Rubakhin SS, Tipton A, Dripps I et al (2019) PACAP and other neuropeptide targets link chronic migraine and opioid-induced hyperalgesia in mouse models. Mol Cell Proteomics 18(12):2447–2458PubMedCrossRef
33.
Akerman S, Goadsby PJ (2015) Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine. Sci Transl Med 7(308):308ra157PubMedCrossRef
34.
Hoffmann J, Miller S, Martins-Oliveira M, Akerman S, Supronsinchai W, Sun H et al (2020) PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache? Pain 161(7):1670–1681PubMedPubMedCentralCrossRef
35.
Ashina M, Doležil D, Bonner JH, Zhou L, Klatt J, Picard H et al (2021) A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia 41(1):33–44PubMedCrossRef
36.
Guo Z, Czerpaniak K, Zhang J, Cao YQ (2021) Increase in trigeminal ganglion neurons that respond to both calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide in mouse models of chronic migraine and posttraumatic headache. Pain 162(5):1483–1499PubMedPubMedCentralCrossRef
37.
Farajdokht F, Babri S, Karimi P, Alipour MR, Bughchechi R, Mohaddes G (2017) Chronic ghrelin treatment reduced photophobia and anxiety-like behaviors in nitroglycerin- induced migraine: role of pituitary adenylate cyclase-activating polypeptide. Eur J Neurosci 45(6):763–772PubMedCrossRef
38.
Farajdokht F, Mohaddes G, Shanehbandi D, Karimi P, Babri S (2018) Ghrelin attenuated hyperalgesia induced by chronic nitroglycerin: CGRP and TRPV1 as targets for migraine management. Cephalalgia 38(11):1716–1730PubMedCrossRef
39.
Sándor K, Kormos V, Botz B, Imreh A, Bölcskei K, Gaszner B et al (2010) Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase-activating polypeptide deficient mice. Neuropeptides 44(5):363–371PubMedCrossRef
40.
Dogrukol-Ak D, Tore F, Tuncel N (2004) Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects. Curr Pharm Des 10(12):1325–1340PubMedCrossRef
41.
42.
Robert C, Bourgeais L, Arreto C-D, Condes-Lara M, Noseda R, Jay T et al (2013) Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. J Neurosci 33(20):8827–8840PubMedPubMedCentralCrossRef
43.
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(2–3):121–126PubMedCrossRef
44.
Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L et al (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164(1):567–574PubMedCrossRef
45.
Spongier D, Waeber C, Pantaloni C, Holsboer F, Bockaert J, Seeburgt PH et al (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365(6442):170–175CrossRef
46.
Armstead WM (1996) Role of ATP-sensitive K+ channels in cGMP-mediated pial artery vasodilation. Am J Physiol 270(2 Pt 2):H423-6PubMed
47.
Wellman GC, Quayle JM, Standen NB (1998) ATP-sensitive K+ channel activation by calcitonin gene-related peptide and protein kinase A in pig coronary arterial smooth muscle. J Physiol 507(Pt 1):117–29PubMedPubMedCentralCrossRef
48.
Wienholtz NKF, Christensen CE, Zhang DG, Coskun H, Ghanizada H, Al-Karagholi MAM et al (2021) Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial. Cephalalgia 41(6):731–748PubMedCrossRef
49.
50.
Muzzi M, Buonvicino D, De Cesaris F, Chiarugi A (2017) Acute and chronic triptan exposure neither alters rodent cerebral blood flow nor worsens ischemic brain injury. Neuroscience 6(340):1–7CrossRef
51.
Dickson L, Finlayson K (2009) VPAC and PAC receptors: From ligands to function. Pharmacol Ther 121(3):294–316PubMedCrossRef
52.
Hou M, Uddman R, Tajti J, Edvinsson L (2003) Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. Brain Res 964(2):179–186PubMedCrossRef
53.
Knutsson M, Edvinsson L (2002) Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. NeuroReport 13(4):507–509PubMedCrossRef
54.
Chan KY, Baun M, De Vries R, Van Den Bogaerdt AJ, Dirven CMF, Danser AHJ et al (2011) Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. Cephalalgia 31(2):181–189PubMedCrossRef
55.
Boni L, Ploug K, Olesen J, Jansen-Olesen I, Gupta S (2009) The in vivo effect of VIP, PACAP-38 and PACAP-27 and mRNA expression of their receptors in rat middle meningeal artery. Cephalalgia 29(8):837–847PubMedCrossRef
56.
Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP (2008) Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 123(3):398–410PubMedPubMedCentralCrossRef
57.
Tajti J, Tuka B, Botz B, Helyes Z, Vecsei L (2015) Role of pituitary adenylate cyclase-activating polypeptide in nociception and migraine. CNS Neurol Disord Drug Targets 14(4):540–553PubMedCrossRef
58.
Fahrenkrug J, Hannibal J, Tams J, Georg B (2000) Immunohistochemical localization of the VIP1 receptor (VPAC1R) in rat cerebral blood vessels: Relation to PACAP and VIP containing nerves. J Cereb Blood Flow Metab 20(8):1205–1214PubMedCrossRef
59.
Schmidt-Choudhury A, Furuta GT, Galli SJ, Schmidt WE, Wershil BK (1999) Mast cells contribute to PACAP-induced dermal oedema in mice. Regul Pept 82(1–3):65–69PubMedCrossRef
60.
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22(1):54–61PubMedCrossRef
61.
Thomsen LL, Kruuse C, Iversen HK, Olesen J (1994) A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1(1):73–80PubMedCrossRef
62.
Ben Aissa M, Tipton AF, Bertels Z, Gandhi R, Moye LS, Novack M et al (2018) Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia 38(8):1471–1484PubMedCrossRef
63.
Brennum J, Brinck T, Schriver L, Wanscher B, SoelbergSørensen P, Tfelt-Hansen P et al (1996) Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache. Eur J Neurol 3(1):23–28CrossRef
64.
Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ (2020) Gepants, calcitonin-gene-related peptide receptor antagonists. Curr Opin Neurol 33(3):1CrossRef
65.
Christensen SLT, Petersen S, Sørensen DB, Olesen J, Jansen-Olesen I (2016) Infusion of low dose glyceryl trinitrate has no consistent effect on burrowing behavior, running wheel activity and light sensitivity in female rats. J Pharmacol Toxicol Methods 1(80):43–50CrossRef
Metadata
Title
PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine
Authors
Song Guo
Charlotte Ernstsen
Anders Hay-Schmidt
David Møbjerg Kristensen
Messoud Ashina
Jes Olesen
Sarah Louise Christensen
Publication date
01-12-2022
Publisher
Springer Milan
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/s10194-022-01523-8

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