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

Roberto De Icco, Rosaria Greco, Chiara Demartini, Pietro Vergobbi, Annamaria Zanaboni, Elena Tumelero, Angelo Reggiani, Natalia Realini, Grazia Sances, Valentina Grillo, Marta Allena, Cristina Tassorelli, Roberto De Icco, Rosaria Greco, Chiara Demartini, Pietro Vergobbi, Annamaria Zanaboni, Elena Tumelero, Angelo Reggiani, Natalia Realini, Grazia Sances, Valentina Grillo, Marta Allena, Cristina Tassorelli

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.

Conflict of interest statement

G. Sances received honoraria for participation in advisory boards or for oral presentations from Eli-Lilly and Novartis. C. Tassorelli received honoraria for participation in advisory boards or for oral presentations from Allergan, ElectroCore, Eli-Lilly, Novartis, and Teva. C. Tassorelli has no ownership interest and does not own stocks of any pharmaceutical company. C. Tassorelli serves as Chief Section Editor of Frontiers in Neurology—Section Headache Medicine and Facial Pain and on the editorial board of The Journal of Headache and Pain. The remaining authors have no conflicts of interest to declare.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

Figures

Figure 1.
Figure 1.
Flow diagram showing the phases of the study. NTG, nitroglycerin 0.9 mg sublingual.
Figure 2.
Figure 2.
Time course of plasma AEA levels after NTG administration in MIG and HC groups. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after nitroglycerin (NTG) administration (0.9 mg sublingual). MIG: subjects with episodic migraine (n = 24); HC: healthy controls (n = 19). Statistical analysis: 2-factor ANOVA for repeated measures (factor “GROUP” with 2 levels: MIG vs HC; factor “TIME” with 4 levels: Baseline, T30, T60, T120). TIME: P = 0.022; GROUP: P = 0.779; TIME × GROUP: P = 0.671. Δ = post hoc analysis: P < 0.050 vs Baseline (the color identifies the group). AEA, anandamide; ANOVA, analysis of variance.
Figure 3.
Figure 3.
Time course of plasma PEA levels after NTG administration in MIG and HC groups. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after nitroglycerin (NTG) administration (0.9 mg sublingual). MIG: subjects with episodic migraine (n = 24); HC: healthy controls (n = 19). Statistical analysis: 2-factor ANOVA for repeated measures (factor “GROUP” with 2 levels: MIG vs HC; factor “TIME” with 4 levels: Baseline, T30, T60, T120). TIME: P = 0.009; GROUP: P = 0.035; TIME × GROUP: P = 0.028. Δ = post hoc analysis: P < 0.050 vs Baseline (the color identifies the group). ANOVA, analysis of variance; PEA, palmitoylethanolamide.
Figure 4.
Figure 4.
Time course of plasma AEA and PEA levels after NTG administration in MIG+ and MIG− subjects. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after nitroglycerin (NTG) administration (0.9 mg sublingual). MIG+: subjects with episodic migraine and a positive migraine-induction test (n = 16). MIG−: subjects with episodic migraine and a negative migraine-induction test (n = 8); Statistical analysis: 2-factor ANOVA for repeated measures (factor “HEADACHE” with 2 levels: MIG+ vs MIG−; factor “TIME” with 4 levels: Baseline, T30, T60, T120): Plasma AEA levels (A): TIME: P = 0.169; HEADACHE: P = 0.909; TIME × HEADACHE: P = 0.872. Plasma PEA levels (B): TIME: P = 0.021; HEADACHE: P = 0.341; TIME × HEADACHE: P = 0.513. AEA, anandamide; ANOVA, analysis of variance; PEA, palmitoylethanolamide.
Figure 5.
Figure 5.
Changes in RTh induced by NTG administration in MIG and HC groups. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). MIG: subjects with episodic migraine (n = 24); HC: healthy controls (n = 19). Statistical analysis: 2-factor ANOVA for repeated measures (factor “GROUP” with 2 levels: MIG vs HC; factor “TIME” with 4 levels: Baseline, T30, T60, T120). TIME: P = 0.009; GROUP: P = 0.001; TIME × GROUP: P = 0.001. Δ = post hoc analysis: P < 0.050 vs Baseline (the color identifies the group). ANOVA, analysis of variance; NTG, nitroglycerin; RTh, reflex threshold.
Figure 6.
Figure 6.
Changes in TST induced by NTG administration in MIG and HC groups. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). MIG: subjects with episodic migraine (n = 24); HC: healthy controls (n = 19). Statistical analysis: 2-factor ANOVA for repeated measures (factor “GROUP” with 2 levels: MIG vs HC; factor “TIME” with 4 levels: Baseline, T30, T60, T120). TIME: P = 0.125; GROUP: P = 0.001; TIME × GROUP: P = 0.001. Δ = post hoc analysis: P < 0.050 vs Baseline (the color identifies the group). ANOVA, analysis of variance; NTG, nitroglycerin; TST, temporal summation threshold.
Figure 7.
Figure 7.
Changes in RTh and TST after NTG administration in MIG+ and MIG− subjects. T30, T60, and T120: evaluations at 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). MIG+: subjects with episodic migraine and a positive migraine-induction test (n = 16). MIG−: subjects with episodic migraine and a negative migraine-induction test (n = 8); Statistical analysis: 2-factor ANOVA for repeated measures (factor “HEADACHE” with 2 levels: MIG+ vs MIG−; factor “TIME” with 4 levels: Baseline, T30, T60, T120): RTh (A): TIME: P = 0.128; HEADACHE: P = 0.568; TIME × HEADACHE: P = 0.528. TST (B): TIME: P = 0.001; HEADACHE: P = 0.549; TIME × HEADACHE: P = 0.858. ANOVA, analysis of variance; NTG, nitroglycerin; RTh, reflex threshold; TST, temporal summation threshold.
Figure 8.
Figure 8.
Changes in endocannabinoid levels and neurophysiological parameters recorded at migraine onset and 1 hour later in migraine subjects showing a positive response to the migraine-induction test within the 180-minute in-hospital observation period. Data from migraine subjects showing a positive migraine-induction test response within the 180-minute in-hospital observation period (MIG+ subgroup, n = 13). T-MIG: evaluation at migraine onset; T-MIG-1h: evaluation 1 hour after migraine onset. Statistical analysis: 1-factor ANOVA for repeated measures (factor “TIME” with 3 levels: Baseline, T-MIG, T-MIG-1h): AEA (A): TIME: P = 0.184. PEA (B): TIME: P = 0.035. RTh (C): TIME: P = 0.035. TST (D): TIME: P = 0.001. Δ = post hoc analysis: P < 0.050 vs Baseline. AEA, anandamide; ANOVA, analysis of variance; PEA, palmitoylethanolamide; RTh, reflex threshold.

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