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

Edvinsson, Jacob C.A. ; Reducha, Philip V. ; Sheykhzade, Majid ; Warfvinge, Karin LU orcid ; Haanes, Kristian A. and Edvinsson, Lars LU (2021) In Molecular Pain 17.
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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CGRP, migraine, neurokinin, Substance P, trigeminal system
in
Molecular Pain
volume
17
publisher
BioMed Central (BMC)
external identifiers
  • pmid:34898306
  • scopus:85121322672
ISSN
1744-8069
DOI
10.1177/17448069211059400
language
English
LU publication?
yes
id
af43be75-580c-49d4-89e8-57e5156f00a2
date added to LUP
2022-01-26 11:31:31
date last changed
2024-03-23 17:36:17
@article{af43be75-580c-49d4-89e8-57e5156f00a2,
  abstract     = {{<p>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.</p>}},
  author       = {{Edvinsson, Jacob C.A. and Reducha, Philip V. and Sheykhzade, Majid and Warfvinge, Karin and Haanes, Kristian A. and Edvinsson, Lars}},
  issn         = {{1744-8069}},
  keywords     = {{CGRP; migraine; neurokinin; Substance P; trigeminal system}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Pain}},
  title        = {{Neurokinins and their receptors in the rat trigeminal system : Differential localization and release with implications for migraine pain}},
  url          = {{http://dx.doi.org/10.1177/17448069211059400}},
  doi          = {{10.1177/17448069211059400}},
  volume       = {{17}},
  year         = {{2021}},
}