The 'headache tree' via umbellulone and TRPA1 activates the trigeminovascular system

• Published in: Brain (London, England : 1878) England : 1878), 2012-02, Vol.135 (2), p.376-390
• Main Authors: Nassini, Romina, Materazzi, Serena, Vriens, Joris, Prenen, Jean, Benemei, Silvia, De Siena, Gaetano, la Marca, Giancarlo, Andrè, Eunice, Preti, Delia, Avonto, Cristina, Sadofsky, Laura, Di Marzo, Vincenzo, De Petrocellis, Luciano, Dussor, Greg, Porreca, Frank, Taglialatela-Scafati, Orazio, Appendino, Giovanni, Nilius, Bernd, Geppetti, Pierangelo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bridged Bicyclo Compounds - pharmacology; Calcitonin Gene-Related Peptide - metabolism; Cyclohexanones - pharmacology; Dura Mater - blood supply; Dura Mater - drug effects; Dura Mater - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; HEK293 Cells; Humans; Male; Medical sciences; Mice; Mice, Transgenic; Monoterpenes; Nervous system (semeiology, syndromes); Neurology; Plant Extracts - pharmacology; Rats; Rats, Sprague-Dawley; Transient Receptor Potential Channels - genetics; Transient Receptor Potential Channels - metabolism; Trigeminal Ganglion - cytology; Trigeminal Ganglion - drug effects; Trigeminal Ganglion - metabolism; Trigeminal Nerve - drug effects; Trigeminal Nerve - metabolism; TRPA1 Cation Channel; Umbellularia; Umbellularia californica
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awr272

The California bay laurel or Umbellularia californica (Hook. & Arn.) Nutt., is known as the 'headache tree' because the inhalation of its vapours can cause severe headache crises. However, the underlying mechanism of the headache precipitating properties of Umbellularia californica is unknown. The monoterpene ketone umbellulone, the major volatile constituent of the leaves of Umbellularia californica, has irritating properties, and is a reactive molecule that rapidly binds thiols. Thus, we hypothesized that umbellulone stimulates the transient receptor potential ankyrin 1 channel in a subset of peptidergic, nocioceptive neurons, activating the trigeminovascular system via this mechanism. Umbellulone, from µM to sub-mM concentrations, selectively stimulated transient receptor potential ankyrin 1-expressing HEK293 cells and rat trigeminal ganglion neurons, but not untransfected cells or neurons in the presence of the selective transient receptor potential ankyrin 1 antagonist, HC-030031. Umbellulone evoked a calcium-dependent release of calcitonin gene-related peptide from rodent trigeminal nerve terminals in the dura mater. In wild-type mice, umbellulone elicited excitation of trigeminal neurons and released calcitonin gene-related peptide from sensory nerve terminals. These two responses were absent in transient receptor potential ankyrin 1 deficient mice. Umbellulone caused nocioceptive behaviour after stimulation of trigeminal nerve terminals in wild-type, but not transient receptor potential ankyrin 1 deficient mice. Intranasal application or intravenous injection of umbellulone increased rat meningeal blood flow in a dose-dependent manner; a response selectively inhibited by systemic administration of transient receptor potential ankyrin 1 or calcitonin gene-related peptide receptor antagonists. These data indicate that umbellulone activates, through a transient receptor potential ankyrin 1-dependent mechanism, the trigeminovascular system, thereby causing nocioceptive responses and calcitonin gene-related peptide release. Pharmacokinetics of umbellulone, given by either intravenous or intranasal administration, suggest that transient receptor potential ankyrin 1 stimulation, which eventually results in meningeal vasodilatation, may be produced via two different pathways, depending on the dose. Transient receptor potential ankyrin 1 activation may either be caused directly by umbellulone, which diffuses from the nasal mucosa to perivascular nerve termi