omega-agatoxin-iva and Migraine-with-Aura

On trigeminal ganglion neurons, pain-sensing P2X3 receptors are constitutively inhibited by brain natriuretic peptide via its natriuretic peptide receptor-A. This inhibition is associated with increased P2X3 serine phosphorylation and receptor redistribution to non-lipid raft membrane compartments. The natriuretic peptide receptor-A antagonist anantin reverses these effects. We studied whether P2X3 inhibition is dysfunctional in a genetic familial hemiplegic migraine type-1 model produced by introduction of the human pathogenic R192Q missense mutation into the mouse CACNA1A gene (knock-in phenotype). This model faithfully replicates several properties of familial hemiplegic migraine type-1, with gain-of-function of CaV2.1 Ca(2+) channels, raised levels of the algogenic peptide calcitonin gene-related peptide, and enhanced activity of P2X3 receptors in trigeminal ganglia.. In knock-in neurons, anantin did not affect P2X3 receptor activity, membrane distribution, or serine phosphorylation level, implying ineffective inhibition by the constitutive brain natriuretic peptide/natriuretic peptide receptor-A pathway. However, expression and functional properties of this pathway remained intact together with its ability to downregulate TRPV1 channels. Reversing the familial hemiplegic migraine type-1 phenotype with the CaV2.1-specific antagonist, ω-agatoxin IVA restored P2X3 activity to wild-type level and enabled the potentiating effects of anantin again. After blocking calcitonin gene-related peptide receptors, P2X3 receptors exhibited wild-type properties and were again potentiated by anantin.. P2X3 receptors on mouse trigeminal ganglion neurons are subjected to contrasting modulation by inhibitory brain natriuretic peptide and facilitatory calcitonin gene-related peptide that both operate via complex intracellular signaling. In the familial hemiplegic migraine type-1 migraine model, the action of calcitonin gene-related peptide appears to prevail over brain natriuretic peptide, thus suggesting that peripheral inhibition of P2X3 receptors becomes insufficient and contributes to trigeminal pain sensitization.

Topics: Animals; Calcitonin Gene-Related Peptide Receptor Antagonists; Disease Models, Animal; Gene Knock-In Techniques; Mice; Migraine with Aura; Models, Biological; Natriuretic Peptide, Brain; omega-Agatoxin IVA; Peptides, Cyclic; Phenotype; Purinergic P2X Receptor Antagonists; Receptors, Atrial Natriuretic Factor; Receptors, Calcitonin Gene-Related Peptide; Receptors, Purinergic P2X3; Sensory Receptor Cells; Trigeminal Ganglion; TRPV Cation Channels

Blockers of L-, N-, and P/Q-type voltage-gated calcium channels (VGCCs) were topically applied to the cortical surface of anaesthetized adult rats to study their role in cortical spreading depression (CSD), a correlate of the migraine aura. By pricking the brain, single CSD could still be elicited after blockade of the three different types of VGCCs as in the untreated brain. Topical KCl application to the untreated cortex resulted in repetitive CSD. However, after application of blockers at either L-, or N-, or P/Q-type VGCCs to the cortical surface, application of KCl elicited only one or very few CSD, and their repetition rate was dramatically reduced. The results suggest that cortical excitability resulting in repetitive CSD is markedly influenced by N- and P/Q-type VGCCs and less by L-type VGCCs.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Cerebral Cortex; Cortical Spreading Depression; Male; Migraine with Aura; Nimodipine; omega-Agatoxin IVA; omega-Conotoxins; Potassium Chloride; Rats; Rats, Wistar