{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:46:49Z","timestamp":1784634409288,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Teva Pharmaceuticals"},{"name":"the Alexander von Humboldt Foundation (Research Group Linkage Program between the Institutes of Physiology of the FAU Erlangen-N\u00fcrnberg and the University of Szeged)"},{"name":"the Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg within the funding program \u201cOpen Access Publication Funding\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which are characteristic pathophysiological changes accompanying severe primary headaches. To further decipher the effects of fremanezumab that underlie these antinociceptive effects in rats, immunohistochemistry and ELISA techniques were used to analyse the content and concentration of CGRP in the trigeminal ganglion, as well as the ratio of trigeminal ganglion neurons which are immunoreactive to CGRP and CGRP receptor components, 1\u201310 days after subcutaneous injection of fremanezumab (30 mg\/kg) compared to an isotype control antibody. After fremanezumab treatment, the fraction of trigeminal ganglion neurons which were immunoreactive to CGRP and the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was significantly lowered compared to the control. The content and concentration of CGRP in trigeminal ganglia were not significantly changed. A long-lasting reduction in CGRP receptors expressed in trigeminal afferents may contribute to the attenuation of CGRP signalling and antinociceptive effects of monoclonal anti-CGRP antibodies in rats.<\/jats:p>","DOI":"10.3390\/ijms241713471","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T09:44:46Z","timestamp":1693388686000},"page":"13471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Anti-Calcitonin Gene-Related Peptide (Anti-CGRP) Antibody Fremanezumab Reduces Trigeminal Neurons Immunoreactive to CGRP and CGRP Receptor Components in Rats"],"prefix":"10.3390","volume":"24","author":[{"given":"Birgit","family":"Vogler","sequence":"first","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Friedrich-Alexander-University, D-91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Friedrich-Alexander-University, D-91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly D.","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals, Redwood City, CA 94063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Stratton","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals, Redwood City, CA 94063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9941-8188","authenticated-orcid":false,"given":"M\u00e1ria","family":"Dux","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8099-3860","authenticated-orcid":false,"given":"Karl","family":"Messlinger","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Friedrich-Alexander-University, D-91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1056\/NEJMoa1709038","article-title":"Fremanezumab for the Preventive Treatment of Chronic Migraine","volume":"377","author":"Silberstein","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2487","DOI":"10.1212\/WNL.0000000000010600","article-title":"Long-Term Safety, Tolerability, and Efficacy of Fremanezumab in Migraine: A Randomized Study","volume":"95","author":"Goadsby","year":"2020","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s10194-022-01431-x","article-title":"European Headache Federation Guideline on the Use of Monoclonal Antibodies Targeting the Calcitonin Gene Related Peptide Pathway for Migraine Prevention\u20142022 Update","volume":"23","author":"Sacco","year":"2022","journal-title":"J. Headache Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ejphar.2004.07.035","article-title":"Calcitonin Gene-Related Peptide and Its Role in Migraine Pathophysiology","volume":"500","author":"Arulmani","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1046\/j.1468-2982.2002.00310.x","article-title":"CGRP May Play a Causative Role in Migraine","volume":"22","author":"Lassen","year":"2002","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1001\/jamaneurol.2018.1675","article-title":"Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial","volume":"75","author":"Vollesen","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10587","DOI":"10.1523\/JNEUROSCI.2211-17.2017","article-title":"Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (A\u03b4) But Not Unmyelinated (C) Meningeal Nociceptors","volume":"37","author":"Strassman","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s10194-019-1055-3","article-title":"C-Fibers May Modulate Adjacent A\u03b4-Fibers through Axon-Axon CGRP Signaling at Nodes of Ranvier in the Trigeminal System","volume":"20","author":"Edvinsson","year":"2019","journal-title":"J. Headache Pain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/s41467-022-28204-z","article-title":"Schwann Cell Endosome CGRP Signals Elicit Periorbital Mechanical Allodynia in Mice","volume":"13","author":"Nassini","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1111\/j.1526-4610.2012.02212.x","article-title":"CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation","volume":"52","author":"Messlinger","year":"2012","journal-title":"Headache"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/head.13529","article-title":"CGRP and the Trigeminal System in Migraine","volume":"59","author":"Iyengar","year":"2019","journal-title":"Headache"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1097\/j.pain.0000000000000831","article-title":"The Role of Calcitonin Gene-Related Peptide in Peripheral and Central Pain Mechanisms Including Migraine","volume":"158","author":"Iyengar","year":"2017","journal-title":"Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1177\/0333102419840780","article-title":"A New Era for Migraine: Pharmacokinetic and Pharmacodynamic Insights into Monoclonal Antibodies with a Focus on Galcanezumab, an Anti-CGRP Antibody","volume":"39","author":"Kielbasa","year":"2019","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Dux, M., Vogler, B., Kuhn, A., Mackenzie, K.D., Stratton, J., and Messlinger, K. (2022). The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow. Cells, 11.","DOI":"10.3390\/cells11111768"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3390\/neurolint15020039","article-title":"Semi-Automated Recording of Facial Sensitivity in Rat Demonstrates Antinociceptive Effects of the Anti-CGRP Antibody Fremanezumab","volume":"15","author":"Benedicter","year":"2023","journal-title":"Neurol. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1111\/head.13064","article-title":"CGRP and Its Receptors","volume":"57","author":"Hay","year":"2017","journal-title":"Headache"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"31438","DOI":"10.1074\/jbc.M005604200","article-title":"CGRP-RCP, a Novel Protein Required for Signal Transduction at Calcitonin Gene-Related Peptide and Adrenomedullin Receptors","volume":"275","author":"Evans","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/30666","article-title":"RAMPs Regulate the Transport and Ligand Specificity of the Calcitonin-Receptor-like Receptor","volume":"393","author":"McLatchie","year":"1998","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1002\/cne.21607","article-title":"Calcitonin Receptor-like Receptor (CLR), Receptor Activity-Modifying Protein 1 (RAMP1), and Calcitonin Gene-Related Peptide (CGRP) Immunoreactivity in the Rat Trigeminovascular System: Differences between Peripheral and Central CGRP Receptor Distribution","volume":"507","author":"Lennerz","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.neuroscience.2010.05.016","article-title":"Differential Distribution of Calcitonin Gene-Related Peptide and Its Receptor Components in the Human Trigeminal Ganglion","volume":"169","author":"Eftekhari","year":"2010","journal-title":"Neuroscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1177\/0333102421989601","article-title":"Anti-CGRP Monoclonal Antibodies for Migraine Prevention: A Systematic Review and Likelihood to Help or Harm Analysis","volume":"41","author":"Drellia","year":"2021","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1177\/0333102418786261","article-title":"Current Understanding of Trigeminal Ganglion Structure and Function in Headache","volume":"39","author":"Messlinger","year":"2019","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_23","first-page":"431","article-title":"Cross-Talk Signaling in the Trigeminal Ganglion: Role of Neuropeptides and Other Mediators","volume":"127","author":"Messlinger","year":"2020","journal-title":"J. Neural Transm. Vienna Austria 1996"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1007\/s12031-020-01493-z","article-title":"Expression of the CGRP Family of Neuropeptides and Their Receptors in the Trigeminal Ganglion","volume":"70","author":"Edvinsson","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/acn3.197","article-title":"A Second Trigeminal CGRP Receptor: Function and Expression of the AMY1 Receptor","volume":"2","author":"Walker","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1177\/0333102418765787","article-title":"Molecular Studies of CGRP and the CGRP Family of Peptides in the Central Nervous System","volume":"39","author":"Hendrikse","year":"2019","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2174\/13892037113149990057","article-title":"Role of CGRP-Receptor Component Protein (RCP) in CLR\/RAMP Function","volume":"14","author":"Dickerson","year":"2013","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1523\/JNEUROSCI.1137-21.2022","article-title":"A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models","volume":"42","author":"Paige","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/S1474-4422(16)30293-9","article-title":"Sex Differences in the Epidemiology, Clinical Features, and Pathophysiology of Migraine","volume":"16","author":"Vetvik","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1177\/0333102420974362","article-title":"Sex Differences in Prevalence of Migraine Trigger Factors: A Cross-Sectional Study","volume":"41","author":"Verhagen","year":"2021","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1111\/ene.15778","article-title":"Sex Differences in Clinical Characteristics of Migraine and Its Burden: A Population-Based Study","volume":"30","author":"Chalmer","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/j.1526-4610.2011.01903.x","article-title":"Sex-Related Differences in Animal Models of Migraine Headache","volume":"51","author":"Bolay","year":"2011","journal-title":"Headache"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s10194-021-01383-8","article-title":"Migraine-Relevant Sex-Dependent Activation of Mouse Meningeal Afferents by TRPM3 Agonists","volume":"23","author":"Krivoshein","year":"2022","journal-title":"J. Headache Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1038\/s41467-022-33835-3","article-title":"TRPM8 Contributes to Sex Dimorphism by Promoting Recovery of Normal Sensitivity in a Mouse Model of Chronic Migraine","volume":"13","author":"Giorgi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.1523\/JNEUROSCI.0364-19.2019","article-title":"Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models","volume":"39","author":"Avona","year":"2019","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13471\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:43:15Z","timestamp":1760128995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,30]]},"references-count":35,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713471"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713471","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,30]]}}}