Abstract
Aim
Meningeal nociceptors within the trigeminal ganglion are important contributors to migraine pathogenesis because they transmit pain signals from the dura mater to the central nervous system. As such, pharmacological interventions that target these peripheral neurons might offer new avenues for migraine treatment. In this context, ATP-sensitive potassium (KATP) channels have garnered increasing attention as potential modulators of meningeal nociception. Human experimental studies support this hypothesis, showing that intravenous infusion of levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine and mild, transient headache in healthy adults. However, the precise anatomical site and mechanism of action remain incompletely understood.
Methods
To address these gaps, we conducted in vivo single-unit electrophysiological recordings of 36 meningeal nociceptors (23 Aδ- and 13 C-fibers) in the trigeminal ganglion of anesthetized male and female rats. We measured spontaneous firing rates before and up to four hours after a 20-minute continuous intracarotid infusion of levcromakalim (1.43 mg/kg or 0.14 mg/kg) or vehicle (71.4% ethanol).
Results
Levcromakalim at 1.43 mg/kg activated nine (69%) of 13 nociceptors, compared with one (11%) of nine in the vehicle group (p = 0.012). Activation rates did not differ between Aδ-fibers (6 of 8, 69%) and C-fibers (3 of 6; 50%; p = 1.00), or between male (6 of 8; 75%) and female animals (3 of 5; 60%; p = 0.61). Moreover, levcromakalim at 0.14 mg/kg activated only three (21%) of 14 nociceptors.
Conclusions
Taken together, our findings demonstrate that KATP channel opening mediates activation of meningeal nociceptors, providing a mechanistic basis for previous observations in humans. The development of KATP channel blockers might therefore hold therapeutic promise for migraine by inhibiting meningeal nociceptors.
Meningeal nociceptors within the trigeminal ganglion are important contributors to migraine pathogenesis because they transmit pain signals from the dura mater to the central nervous system. As such, pharmacological interventions that target these peripheral neurons might offer new avenues for migraine treatment. In this context, ATP-sensitive potassium (KATP) channels have garnered increasing attention as potential modulators of meningeal nociception. Human experimental studies support this hypothesis, showing that intravenous infusion of levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine and mild, transient headache in healthy adults. However, the precise anatomical site and mechanism of action remain incompletely understood.
Methods
To address these gaps, we conducted in vivo single-unit electrophysiological recordings of 36 meningeal nociceptors (23 Aδ- and 13 C-fibers) in the trigeminal ganglion of anesthetized male and female rats. We measured spontaneous firing rates before and up to four hours after a 20-minute continuous intracarotid infusion of levcromakalim (1.43 mg/kg or 0.14 mg/kg) or vehicle (71.4% ethanol).
Results
Levcromakalim at 1.43 mg/kg activated nine (69%) of 13 nociceptors, compared with one (11%) of nine in the vehicle group (p = 0.012). Activation rates did not differ between Aδ-fibers (6 of 8, 69%) and C-fibers (3 of 6; 50%; p = 1.00), or between male (6 of 8; 75%) and female animals (3 of 5; 60%; p = 0.61). Moreover, levcromakalim at 0.14 mg/kg activated only three (21%) of 14 nociceptors.
Conclusions
Taken together, our findings demonstrate that KATP channel opening mediates activation of meningeal nociceptors, providing a mechanistic basis for previous observations in humans. The development of KATP channel blockers might therefore hold therapeutic promise for migraine by inhibiting meningeal nociceptors.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cephalalgia |
| Vol/bind | 45 |
| Udgave nummer | 8 |
| Antal sider | 11 |
| ISSN | 0333-1024 |
| DOI | |
| Status | Udgivet - 2025 |
Bibliografisk note
Publisher Copyright:© International Headache Society 2025. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).