The effects of certain TRP channels and voltage-gated KCNQ/Kv7 channel opener retigabine on calcitonin gene-related peptide release in the trigeminovascular system

Cephalalgia. 2022 Nov;42(13):1375-1386. doi: 10.1177/03331024221114773. Epub 2022 Jul 21.


Background: Calcitonin gene-related peptide release in trigeminovascular system is a pivotal component of neurogenic inflammation underlying migraine pathophysiology. Transient receptor potential channels and voltage-gated KCNQ/Kv7 potassium channels expressed throughout trigeminovascular system are important targets for modulation of calcitonin gene-related peptide release. We investigated the effects of certain transient receptor potential (TRP) channels the vanilloid 1 and 4 (TRPV1 and TRPV4), the ankyrin 1 (TRPA1), and metastatin type 8 (TRPM8), and voltage-gated potassium channel (Kv7) opener retigabine on calcitonin gene-related peptide release from peripheral (dura mater and trigeminal ganglion) and central (trigeminal nucleus caudalis) trigeminal components of rats.

Methods: The experiments were carried out using well-established in-vitro preparations (hemiskull, trigeminal ganglion and trigeminal nucleus caudalis) from male Wistar rats. Agonists and antagonists of TRPV1, TRPV4, TRPA1 and TRPM8 channels, and also retigabine were tested on the in-vitro release of calcitonin gene-related peptide. Calcitonin gene-related peptide concentrations were measured using enzyme-linked immunosorbent assay.

Results: Agonists of these transient receptor potential channels induced calcitonin gene-related peptide release from hemiskull, trigeminal ganglion and trigeminal nucleus caudalis, respectively. The transient receptor potential channels-induced calcitonin gene-related peptide releases were blocked by their specific antagonists and reduced by retigabine. Retigabine also decreased basal calcitonin gene-related peptide releases in all preparations.

Conclusion: Our findings suggest that favorable antagonists of these transient receptor potential channels, or Kv7 channel opener retigabine may be effective in migraine therapy by inhibiting neurogenic inflammation that requires calcitonin gene-related peptide release.

Keywords: CGRP; Migraine; transient receptor potential channels; trigeminovascular system; voltage-gated KCNQ/Kv7 potassium channels.

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Male
  • Migraine Disorders* / drug therapy
  • Neurogenic Inflammation
  • Rats
  • Rats, Wistar
  • TRPV Cation Channels
  • Transient Receptor Potential Channels* / pharmacology
  • Trigeminal Ganglion / metabolism


  • Calcitonin Gene-Related Peptide
  • Transient Receptor Potential Channels
  • TRPV Cation Channels
  • ezogabine
  • Trpv4 protein, rat