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Edvinsson JC, Reducha PV, Sheykhzade M, et al. Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain. Mol Pain. 2021;17:17448069211059400doi: 10.1177/17448069211059400.
Edvinsson, J. C., Reducha, P. V., Sheykhzade, M., Warfvinge, K., Haanes, K. A., & Edvinsson, L. (2021). Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain. Molecular pain, 1717448069211059400. https://doi.org/10.1177/17448069211059400
Edvinsson, Jacob Ca, et al. "Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain." Molecular pain vol. 17 (2021): 17448069211059400. doi: https://doi.org/10.1177/17448069211059400
Edvinsson JC, Reducha PV, Sheykhzade M, Warfvinge K, Haanes KA, Edvinsson L. Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain. Mol Pain. 2021 Jan-Dec;17:17448069211059400. doi: 10.1177/17448069211059400. PMID: 34898306; PMCID: PMC8679402.
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Mol Pain. 2021 Jan-Dec;17:17448069211059400. doi: 10.1177/17448069211059400.

Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.

Molecular pain

Jacob Ca Edvinsson, Philip V Reducha, Majid Sheykhzade, Karin Warfvinge, Kristian A Haanes, Lars Edvinsson

Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 53139University of Copenhagen, Copenhagen, Denmark.
  2. Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Glostrup, Denmark.
  3. Department of Biology, University of Copenhagen, Copenhagen, Denmark.
  4. Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.

PMID: 34898306 PMCID: PMC8679402 DOI: 10.1177/17448069211059400

Abstract

Substance P (SP) and calcitonin gene-related peptide (CGRP) have both been considered potential drug candidates in migraine therapy. In recent years, CGRP receptor inhibition has been established as an effective treatment, in particular as a prophylactic for chronic migraine. Curiously, inhibition of neurokinin receptor 1 (NK1R) failed to alleviate acute migraine attacks in clinical trials, and the neurokinins were consequently abandoned as potential antimigraine candidates. The reason behind this has remained enigmatic.Utilizing immunohistochemistry and semi-quantitative cell counts the expression of neurokinins and their associated receptors was examined in the rat trigeminal ganglion.Immunohistochemistry results revealed SP co-localization in CGRP positive neurons and C-fibres, where it mainly concentrated at boutons. Neurokinin A (NKA) was observed in a population of C-fibres and small neurons where it could co-localize with SP. In contrast, neurokinin B (NKB) did not co-localize with SP and was observed in large/medium sized neurons and Aδ-fibres. All neurokinin receptors (NK1-3R) were found to be expressed in a majority of trigeminal ganglion neurons and A-fibres.The functional release of SP and CGRP in the trigeminovascular system was stimulated with either 60 mM K+ or 100 nM capsaicin and measured with an enzyme-linked immunosorbent assay (ELISA). ELISA results established that SP can be released locally from trigeminovascular system. The released SP was comparatively minor compared to the CGRP release from stimulated dura mater, trigeminal ganglion neurons and fibres. We hypothesize that SP and CGRP signalling pathways may work in tandem to exacerbate painful stimuli in the TGV system.

Keywords: CGRP; Substance P; migraine; neurokinin; trigeminal system

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