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

Abstract

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). Anandamide 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. Nitroglycerin 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 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.

Triggers of migraine: where do we stand?

“…Similar findings have also been reported with auditory evoked potentials [36] and with the evaluation of nociceptive withdrawal reflex [39] and the blink reflex [40], to suggest that the migraine brain is characterized by a lack of habituation of responses evoked by repeated stimuli. Finally, it was demonstrated [41] that responses to peripheral stimulation were reduced in patients with migraine.…”

Clinical Evidence of Cannabinoids in Migraine: A Narrative Review

“…AEA levels increased in both EM patients and healthy controls, whereas PEA increased only in migraine patients, regardless of whether or not a migraine attack was reported. The increased PEA in migraineurs vs. healthy controls presumably reflects migraine-specific mechanisms [ 37 ]. No clinical trials on compounds capable of modulating the ECS (such as FAAH/MAGL inhibitors) are currently available for migraine.…”

Oculo-vestibular signs in experimentally induced migraine attacks: an exploratory analysis

“…The full description of the study population and experimental design is reported in the main study [ 8 ]. Briefly, our sample comprised 24 patients with a diagnosis of episodic migraine (MIG group) and a group of 19 healthy controls (HC group).…”