P/Q-Type Calcium-Channel Blockade in the Periaqueductal Gray Facilitates Trigeminal Nociception: A Functional Genetic Link for Migraine?

Abstract

The discovery of mis-sense mutations in the ␣1A subunit of the P/Q-type calcium channel in patients with familial hemiplegic migraine indicates the potential involvement of dysfunctional ion channels in migraine. The periaqueductal gray (PAG) region of the brainstem modulates craniovascular nociception and, through its role in the descending pain modulation system, may contribute to migraine pathophysiology. In this study we sought to investigate the possible link between the genetic mutations found in migraineurs and the PAG as a modulator of craniovascular nociception. We microinjected the P/Q-type calciumchannel blocker -agatoxin IVA into the rat ventrolateral PAG (vlPAG). We examined its effect on the nociceptive transmission of second-order neurons recorded in the trigeminal nucleus caudalis and activated by stimulation of the parietal dura mater. After injection of agatoxin into the vlPAG (n ϭ 20) responses to dural stimulation were facilitated by 143% ( p Ͻ 0.0001) for A␦-fiber activity and 180% for C-fiber activity ( p Ͻ 0.05). Similarly, spontaneous background activity increased by 163% ( p Ͻ 0.0001). These results demonstrate that P/Q-type calcium channels in the PAG play a role in modulating trigeminal nociception and suggest a role for dysfunctional P/Q-type calcium channels in migraine pathophysiology.

Familial Hemiplegic Migraine

“…1,2,57 There is evidence that Ca V 2.1 channels play an important role in central sensitization in the spinal cord, 25,58 and that Ca V 2.1 channels located in the periaqueductal gray region and in the rostroventromedial medulla play a role in descending inhibitory and facilitatory pathways that regulate trigeminal and spinal pain. 59,60 Moreover, Ca V 2.1 channels are involved in the control of neurotransmitter release from perivascular terminals of meningeal afferents and consequent neurogenic vasodilation. 1,61 Thus, although the consequences of FHM1 mutations on trigeminal nociception remain unexplored, one may predict alterations that probably lead to hyperexcitability of the nociceptive trigeminovascular pathways in FHM1.…”

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

“…Functional imaging of patients has provided evidence for a role of the brainstem, particularly the periaqueductal gray (PAG) region, in attacks of migraine without aura (38,39). Inhibition of P͞Q-type channels in PAG has been shown to facilitate trigeminal nociception, thus pointing out a role of these channels in the descending paininhibitory system that regulates the perception of pain (40). It is not clear whether the localization of the relevant P͞Q channels is presynaptic or postsynaptic, and the mechanism by which their inhibition leads to facilitation (or rather disinhibition) of the second order trigeminal neurons remains unknown.…”

Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca 2+ channel activity and inhibitory synaptic transmission

“…Weakening of descending inhibition or local inhibitory feedback increases the gain of pain signaling (44). In a striking example (45), microinjection of -Aga-IVA into a key nucleus in the descending modulatory pathway, the periaqueductal gray, facilitates firing of TNC relay neurons, providing proof-of-principle that attenuation of P͞Q-type channel activity can remove tonic descending inhibition and thereby enhance pain signaling.…”