Opening of ATP-sensitive potassium channels activates meningeal nociceptors: Implications for the origin of migraine headache

AimMeningeal 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 (K_ATP) channels have garnered increasing attention as potential modulators of meningeal nociception. Human experimental studies support this hypothesis, showing that intravenous infusion of levcromakalim, a K_ATP 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.MethodsTo address these gaps, we conducted <i>in vivo</i> 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).ResultsLevcromakalim at 1.43 mg/kg activated nine (69%) of 13 nociceptors, compared with one (11%) of nine in the vehicle group (<i>p</i> = 0.012). Activation rates did not differ between Aδ-fibers (6 of 8, 69%) and C-fibers (3 of 6; 50%; <i>p</i> = 1.00), or between male (6 of 8; 75%) and female animals (3 of 5; 60%; <i>p</i> = 0.61). Moreover, levcromakalim at 0.14 mg/kg activated only three (21%) of 14 nociceptors.ConclusionsTaken together, our findings demonstrate that K_ATP channel opening mediates activation of meningeal nociceptors, providing a mechanistic basis for previous observations in humans. The development of K_ATP channel blockers might therefore hold therapeutic promise for migraine by inhibiting meningeal nociceptors.