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

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


Romina Nassini

Serena Materazzi

Joris Vriens

Jean Prenen

Silvia Benemei

Gaetano De Siena

Giancarlo la Marca

Eunice Andrè

Delia Preti

Cristina Avonto

Dr Laura Sadofsky
Lecturer in Respiratory Medicine/ Academic lead for postgraduate training in HYMS

Vincenzo Di Marzo

Luciano De Petrocellis

Greg Dussor

Frank Porreca

Orazio Taglialatela-Scafati

Giovanni Appendino

Bernd Nilius

Pierangelo Geppetti


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 terminals in meningeal vessels, or by stimulation of trigeminal endings within the nasal mucosa and activation of reflex pathways. Transient receptor potential ankyrin 1 activation represents a plausible mechanism for Umbellularia californica-induced headache. Present data also strengthen the hypothesis that a series of agents, including chlorine, cigarette smoke, formaldehyde and others that are known to be headache triggers and recently identified as transient receptor potential ankyrin 1 agonists, utilize the activation of this channel on trigeminal nerves to produce head pain.


Nassini, R., Materazzi, S., Vriens, J., Prenen, J., Benemei, S., De Siena, G., …Geppetti, P. (2012). The 'headache tree' via umbellulone and TRPA1 activates the trigeminovascular system. Brain, 135(2), 376-390.

Journal Article Type Article
Online Publication Date Oct 25, 2011
Publication Date Feb 1, 2012
Journal Brain : a journal of neurology
Print ISSN 1460-2156
Electronic ISSN 1460-2156
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 135
Issue 2
Pages 376-390
Keywords Clinical Neurology
Public URL
PMID 22036959