Background & Aims

Ingestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Acetaldehyde, the dehydrogenized metabolite of Ethanol, is a known TRP ankyrin 1 (TRPA1) agonist. The TRPA1 channel is a non-selective cation channel expressed by TRPV1-positive neurons, and a multisensor for a variety of noxious exogenous and endogenous stimuli (1), including reactive oxygen species (ROS), which plays a major role in different models of inflammatory and neuropathic pain. Moreover, TRPA1 has been studied as a valuable therapeutic target for headache and migraine treatment and its activation leads to calcitonin gene-related peptide (CGRP) release. Preclinical and clinical findings have confirmed the crucial role of CGRP as the major mediator of migraine pain (2). TRPA1 and CGRP could have a pivotal role in regulation of migraine like-behaviour following ingestion of alcoholic beverages.

Methods

Periorbital mechanical allodynia (PMA) following systemic ethanol and acetaldehyde was investigated in mice after TRPA1 pharmacological antagonism and global genetic deletion. Mice with selective silencing of the receptor activated modifying protein 1 (RAMP1), a component of the calcitonin gene related peptide (CGRP) receptor, in Schwann cells or selective silencing of TRPA1 in dorsal root ganglion (DRG) neurons or Schwann cells, were used after systemic ethanol and acetaldehyde.

Results

We show in mice that intragastric ethanol administration evokes a sustained PMA that is attenuated by systemic or local alcohol dehydrogenase inhibition, and TRPA1 global deletion, thus indicating the implication of acetaldehyde. Systemic acetaldehyde administration also evokes PMA. Importantly, PMA by both ethanol and acetaldehyde is abrogated by pretreatment with the CGRP receptor antagonist, olcegepant, and a selective silencing of RAMP1 in Schwann cells. PMA by ethanol and acetaldehyde is also attenuated by cyclic AMP, protein kinase A, and nitric oxide inhibition and pretreatment with an antioxidant. Moreover, selective genetic silencing of TRPA1 in Schwann cells or DRG neurons attenuated PMA by ethanol or acetaldehyde.

Conclusions

Results suggest that, in mice, PMA, a response that mimics cutaneous allodynia reported during migraine attacks, is elicited by ethanol via the systemic production of acetaldehyde that, by releasing CGRP, engages the CGRP receptor in Schwann cells. The ensuing cascade of intracellular events results in a Schwann cell TRPA1-dependent oxidative stress generation that eventually targets neuronal TRPA1 to signal allodynia from the periorbital area.

References

1.Bautista DM, Jordt SE, Nikai T, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124(6):1269-1282. doi:10.1016/j.cell.2006.02.023
2.Edvinsson, L. et al. “CGRP as the target of new migraine therapies – successful translation from bench to clinic.” Nature reviews. Neurology vol. 14,6 (2018): 338-350. doi:10.1038/s41582-018-0003-1

Presenting Author

Lorenzo Landini

Poster Authors

Lorenzo Doctor Landini, PhD

Md, Phd

University of Florence

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Migraine