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
; 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.
(Less)
- author
- Edvinsson, Jacob C.A.
; Reducha, Philip V.
; Sheykhzade, Majid
; Warfvinge, Karin
LU
; Haanes, Kristian A.
and Edvinsson, Lars
LU
- organization
- publishing date
- 2021-12
- 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
-
- scopus:85121322672
- pmid:34898306
- 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
- 2024-12-15 20:05:20
@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}},
}