Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks

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 5 0.822) and PEA (P 5 0.182) levels, and for RTh (P 5 0.142) and TST values (P 5 0.150). Anandamide levels increased after NTG administration (P 5 0.022) in both groups, without differences between them (P 5 0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (P 5 0.004), while remaining stable in the HC group. Nitroglycerin administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (P 5 0.046) at T30 and T120, and in TST (P 5 0.001) at all time points. In the HC group, we observed increases in RTh (P 5 0.001) and TST (P 5 0.008), which suggest 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.