TRPM3 activation causes CGRP release in trigeminal neurons : Implications for migraine mechanisms
(2025) In Headache- Abstract
Background: The transient receptor potential melastatin 3 (TRPM3) ion channel has been implicated in sensory modulation and pain transmission and may contribute to migraine pathophysiology through calcitonin gene-related peptide (CGRP) release in the trigeminovascular system. This study aimed to investigate TRPM3 activation and its role in CGRP release, vasodilatory responses, and migraine-relevant behaviors using preclinical models. Methods: Male and female Sprague-Dawley rats were used to evaluate CGRP release from trigeminal ganglia (TG) and dura mater following stimulation with the TRPM3 agonist CIM0216. CGRP levels were quantified using ELISA. Myograph studies assessed vasodilation in the middle cerebral artery (MCA) and middle... (More)
Background: The transient receptor potential melastatin 3 (TRPM3) ion channel has been implicated in sensory modulation and pain transmission and may contribute to migraine pathophysiology through calcitonin gene-related peptide (CGRP) release in the trigeminovascular system. This study aimed to investigate TRPM3 activation and its role in CGRP release, vasodilatory responses, and migraine-relevant behaviors using preclinical models. Methods: Male and female Sprague-Dawley rats were used to evaluate CGRP release from trigeminal ganglia (TG) and dura mater following stimulation with the TRPM3 agonist CIM0216. CGRP levels were quantified using ELISA. Myograph studies assessed vasodilation in the middle cerebral artery (MCA) and middle meningeal artery. Immunohistochemistry was used to examine TRPM3 and CGRP localization in TG, dura mater, MCA, and human dura mater. Potential behavioral responses to subcutaneous CIM0216 administration were assessed via mechanical sensitivity tests. Calcium responses to CIM0216 were investigated on CGRP neurons in the TG of transgenic female mice. Results: TRPM3 channel activation with CIM0216 triggered CGRP release from TG at 100 μM, with indications of enhanced release in female tissues. Immunohistochemistry confirmed colocalization of the TRPM3 channel and CGRP in TG neurons. Additionally, TRPM3 expression was detected in arterial structures, indicating potential involvement in vascular regulation. Although CIM0216 induced CGRP release ex vivo, subcutaneous CIM0216 administration was unable to induce allodynia-like symptoms in rats. Application of CIM0216 induced an increase of cytosolic calcium in trigeminal CGRP neurons. Conclusions: TRPM3 activation triggers CGRP release and vasodilatation. The findings that TRPM3 induced CGRP release support further investigation of TRPM3 as a therapeutic target for migraine.
(Less)
- author
- Reducha, Philip V. ; Nielsen, Lukas K.S. ; Jensen, Mette N. ; Edvinsson, Jacob C.A. LU ; Kazantzi, Spyridoula ; Wæver, Sofia L. ; Lylloff, Tanja ; Westgate, Connar S.J. ; Edvinsson, Lars LU and Haanes, Kristian A.
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- epub
- subject
- keywords
- calcitonin gene-related peptide, enzyme-linked immunosorbent assay, migraine, myograph, transient receptor potential melastatin 3
- in
- Headache
- publisher
- Wiley-Blackwell
- external identifiers
-
- pmid:41133435
- scopus:105019687783
- ISSN
- 0017-8748
- DOI
- 10.1111/head.15082
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.
- id
- 005e65e8-ea04-4d82-aaf9-e05cb25f22a8
- date added to LUP
- 2026-01-16 15:11:05
- date last changed
- 2026-01-30 16:32:12
@article{005e65e8-ea04-4d82-aaf9-e05cb25f22a8,
abstract = {{<p>Background: The transient receptor potential melastatin 3 (TRPM3) ion channel has been implicated in sensory modulation and pain transmission and may contribute to migraine pathophysiology through calcitonin gene-related peptide (CGRP) release in the trigeminovascular system. This study aimed to investigate TRPM3 activation and its role in CGRP release, vasodilatory responses, and migraine-relevant behaviors using preclinical models. Methods: Male and female Sprague-Dawley rats were used to evaluate CGRP release from trigeminal ganglia (TG) and dura mater following stimulation with the TRPM3 agonist CIM0216. CGRP levels were quantified using ELISA. Myograph studies assessed vasodilation in the middle cerebral artery (MCA) and middle meningeal artery. Immunohistochemistry was used to examine TRPM3 and CGRP localization in TG, dura mater, MCA, and human dura mater. Potential behavioral responses to subcutaneous CIM0216 administration were assessed via mechanical sensitivity tests. Calcium responses to CIM0216 were investigated on CGRP neurons in the TG of transgenic female mice. Results: TRPM3 channel activation with CIM0216 triggered CGRP release from TG at 100 μM, with indications of enhanced release in female tissues. Immunohistochemistry confirmed colocalization of the TRPM3 channel and CGRP in TG neurons. Additionally, TRPM3 expression was detected in arterial structures, indicating potential involvement in vascular regulation. Although CIM0216 induced CGRP release ex vivo, subcutaneous CIM0216 administration was unable to induce allodynia-like symptoms in rats. Application of CIM0216 induced an increase of cytosolic calcium in trigeminal CGRP neurons. Conclusions: TRPM3 activation triggers CGRP release and vasodilatation. The findings that TRPM3 induced CGRP release support further investigation of TRPM3 as a therapeutic target for migraine.</p>}},
author = {{Reducha, Philip V. and Nielsen, Lukas K.S. and Jensen, Mette N. and Edvinsson, Jacob C.A. and Kazantzi, Spyridoula and Wæver, Sofia L. and Lylloff, Tanja and Westgate, Connar S.J. and Edvinsson, Lars and Haanes, Kristian A.}},
issn = {{0017-8748}},
keywords = {{calcitonin gene-related peptide; enzyme-linked immunosorbent assay; migraine; myograph; transient receptor potential melastatin 3}},
language = {{eng}},
publisher = {{Wiley-Blackwell}},
series = {{Headache}},
title = {{TRPM3 activation causes CGRP release in trigeminal neurons : Implications for migraine mechanisms}},
url = {{http://dx.doi.org/10.1111/head.15082}},
doi = {{10.1111/head.15082}},
year = {{2025}},
}