Large Conductance Calcium-Activated Potassium Channels (BK_Ca) Modulate Trigeminovascular Nociceptive Transmission

Abstract

Migraine is a common, disabling, neurological problem whose acute management would benefit from the development of purely neurally acting therapies. The trigeminocervical complex is pivotal in nociceptive signaling in migraine, and is an accepted target for putative antimigraine agents. Whole-cell patch-clamp or extracellular recordings were made of trigeminal neurons identified in rat brainstem slices. Bath application of the large conductance calcium-activated potassium (BKCa) channel opener NS1619 caused a dramatic decrease of cell firing that could be reversed by the co-application of iberiotoxin. NS1619 hyperpolarized the resting membrane potential and reduced the frequency of spontaneous action potentials in these neurons. These data suggest the presence of BKCa channels in the trigeminocervical complex. In vivo in cat L-glutamate-evoked firing was facilitated in nociceptive neurons, also responding to stimulation of the superior sagittal sinus, in the trigeminal nucleus caudalis by the BKCa peptide antagonists, iberiotoxin and slotoxin. Of units tested, 70% responded to microiontophoretic application of the blockers, identifying a subpopulation of trigeminal neurons expressing toxin-sensitive BKCa channels. NS1619 inhibited 74% of cells tested, and this was reversed by slotoxin, suggesting that the action of NS1619 in these cells was mediated through BKCa channels. These data are consistent with the presence of BKCa channels in the trigeminal nucleus caudalis that are potential targets for the development of antimigraine treatments, and may also offer insights into receptor mechanisms involved in sensitization and thus allodynia, in migraine.

The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain

“…The BK Ca channel agonist NS1619, a benzimidazolone analog (13,14), was selected to investigate the effect of activation of BK Ca channels on mechanical allodynia in ION-CCI rats. Target injection of 20 µg ( n = 6), 50 µg ( n = 6) and 100 µg ( n = 7) NS1619 dose-dependently increased the mechanical pain threshold in response to the stimulus of Von-Frey hair filaments in the ION-CCI rats (Figure 1(b)).…”

“…Our findings suggested that the reduced expression, not the shifted distribution of BK Ca , might contribute to the increased excitability of sensory neurons in TG. The discrepancy in the trigeminal afferent pathway could probably be explained by its unique characteristic that trigeminal afferents innervate the dura mater projecting to second-order neurons of the trigeminal nucleus caudalis, which is different from the spinal afferent pathway (13–15). In the present study we found the changes in BK Ca observed in the histological studies were not only confined to the maxillary region (second division of the trigeminal nerve, V2) of the TG but found throughout the ganglia.…”

“…BK Ca channels might have no effect on the nociceptive signal transmission in the physiological condition while affecting an anti-allodynic role in trigeminal neuropathic pain state. The suppression of neuronal firing activity by NS1619 can be attributed to the increases of threshold for action potential firing, the prolonged duration of action potential (19), reduction in action potential frequency and the increases in amplitude of AHP (11,13,14,19). Our present studies demonstrate that NS1619 significantly enhanced the mean threshold intensities for evoking action potentials in TG neurons from the ION-CCI rats while failing to affect those from the sham rats.…”

“…BK Ca are expressed intrinsic membrane proteins and are involved in the regulation of neuronal excitability (13)(14)(15)(16)(17). Because of their high conductance, activation of BK Ca channels shortens the action potential duration, enhances the rate of repolarization, reduces the depolarization and contributes to the rapid after-hyperpolarization.…”

Nerve injury increases brain‐derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons

“…BK channel activation results in the negative feedback regulation of membrane excitability, calcium influx, and neurotransmitter release (Scholz et al. 1998; Storer et al. 2009).…”