Migraine/Headache

CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming Caα subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Migraine pathophysiology has been suggested to include dysregulation of the endocannabinoid system (ES). We simultaneously evaluated plasma anandamide (AEA) and palmitoylethanolamide (PEA) levels and spinal sensitization in a validated human model of migraine based on systemic nitroglycerin (NTG) administration.Twenty-four subjects with episodic migraine (MIG) and 19 healthy controls (HC) underwent blood sampling and investigation of nociceptive withdrawal reflex thresholds (RTh: single-stimulus threshold; TST: temporal summation threshold) before and 30 (T30), 60 (T60) and 120 (T120) minutes after sublingual NTG administration (0.9 mg).At baseline, the MIG and HC groups were comparable for plasma AEA (p=0.822) and PEA (p=0.182) levels, and for RTh (p=0.142) and TST values (p=0.150). AEA levels increased after NTG administration (p=0.022) in both groups, without differences between them (p=0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (p=0.004), while remaining stable in the HC group.NTG administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (p=0.046) at T30 and T120, and in TST (p=0.001) at all time points. In the HC group we observed increases in RTh (p=0.001) and TST (p=0.008), which suggests the occurrence of habituation. We found no significant correlations between the ES and neurophysiological parameters.Our findings suggest a role for PEA in the ictal phase of episodic migraine. The ES does not seem to be directly involved in the modulation of NTG-induced central sensitization, which suggests that the observed PEA increase and spinal sensitization are parallel, probably unrelated, phenomena.