Lasmiditan and 5-Hydroxytryptamine in the rat trigeminal system; expression, release and interactions with 5-HT1 receptors
Edvinsson, Jacob C.A. LU ; Maddahi, Aida LU ; Christiansen, Isabella M. ; Reducha, Philip V. ; Warfvinge, Karin LU
; Sheykhzade, Majid
; Edvinsson, Lars
LU
and Haanes, Kristian A.
(2022)
In Journal of Headache and Pain
23(1).
- Abstract
Background: 5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT1B/1D) and ditans (5-HT1F). Methods: Utilizing immunohistochemistry, the localization of 5-HT and of 5-HT1B/1D/1F receptors was examined in rat... (More)
Background: 5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT1B/1D) and ditans (5-HT1F). Methods: Utilizing immunohistochemistry, the localization of 5-HT and of 5-HT1B/1D/1F receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT1B/1D/1F receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release. Results: 5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT1B/1D receptors were expressed in the TG, while the 5-HT1F receptor displayed a weak ir. The 5-HT1D receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT1B-ir was weakly expressed and 5-HT1F-ir was not detected in these fibres. None of the 5-HT1 receptors co-localized with CGRP-ir in C-fibres. 5-HT1D receptor mRNA was the most prominently expressed, followed by the 5-HT1B receptor and lastly the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptor antagonist, GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT1F receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition. Conclusion: This study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT1B/1D receptors and suggests that the 5-HT1F receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT1B/1D receptors in clinically relevant dose regiments.
(Less)
- author
- Edvinsson, Jacob C.A.
LU
; Maddahi, Aida
LU
; Christiansen, Isabella M.
; Reducha, Philip V.
; Warfvinge, Karin
LU
; Sheykhzade, Majid
; Edvinsson, Lars
LU
and Haanes, Kristian A.
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 5-HT, CGRP, Lasmiditan, Migraine, Trigeminal system
- in
- Journal of Headache and Pain
- volume
- 23
- issue
- 1
- article number
- 26
- publisher
- Springer
- external identifiers
-
- pmid:35177004
- scopus:85124774984
- ISSN
- 1129-2369
- DOI
- 10.1186/s10194-022-01394-z
- language
- English
- LU publication?
- no
- id
- eb87c52b-cfeb-4b90-8289-a425145941b3
- date added to LUP
- 2022-04-12 15:17:47
- date last changed
- 2024-04-21 19:08:39
@article{eb87c52b-cfeb-4b90-8289-a425145941b3,
abstract = {{<p>Background: 5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT<sub>1B/1D/1F</sub> receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT<sub>1B/1D</sub>) and ditans (5-HT<sub>1F</sub>). Methods: Utilizing immunohistochemistry, the localization of 5-HT and of 5-HT<sub>1B/1D/1F</sub> receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT<sub>1B/1D/1F</sub> receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release. Results: 5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT<sub>1B/1D</sub> receptors were expressed in the TG, while the 5-HT<sub>1F</sub> receptor displayed a weak ir. The 5-HT<sub>1D</sub> receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT<sub>1B</sub>-ir was weakly expressed and 5-HT<sub>1F</sub>-ir was not detected in these fibres. None of the 5-HT<sub>1</sub> receptors co-localized with CGRP-ir in C-fibres. 5-HT<sub>1D</sub> receptor mRNA was the most prominently expressed, followed by the 5-HT<sub>1B</sub> receptor and lastly the 5-HT<sub>1F</sub> receptor. The 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptor antagonist, GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT<sub>1F</sub> receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition. Conclusion: This study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT<sub>1B/1D</sub> receptors and suggests that the 5-HT<sub>1F</sub> receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT<sub>1B/1D</sub> receptors in clinically relevant dose regiments.</p>}},
author = {{Edvinsson, Jacob C.A. and Maddahi, Aida and Christiansen, Isabella M. and Reducha, Philip V. and Warfvinge, Karin and Sheykhzade, Majid and Edvinsson, Lars and Haanes, Kristian A.}},
issn = {{1129-2369}},
keywords = {{5-HT; CGRP; Lasmiditan; Migraine; Trigeminal system}},
language = {{eng}},
number = {{1}},
publisher = {{Springer}},
series = {{Journal of Headache and Pain}},
title = {{Lasmiditan and 5-Hydroxytryptamine in the rat trigeminal system; expression, release and interactions with 5-HT<sub>1</sub> receptors}},
url = {{http://dx.doi.org/10.1186/s10194-022-01394-z}},
doi = {{10.1186/s10194-022-01394-z}},
volume = {{23}},
year = {{2022}},
}