The 'headache tree' via umbellulone and TRPA1 activates the trigeminovascular system.
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.
Department of Preclinical and Clinical Pharmacology and Headache Centre, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Romina
R
Nassini
Serena
S
Materazzi
Joris
J
Vriens
Jean
J
Prenen
Silvia
S
Benemei
Gaetano
G
De Siena
Giancarlo
G
la Marca
Eunice
E
Andrè
Delia
D
Preti
Cristina
C
Avonto
Laura
L
Sadofsky
Vincenzo
V
Di Marzo
Luciano
L
De Petrocellis
Greg
G
Dussor
Frank
F
Porreca
Orazio
O
Taglialatela-Scafati
Giovanni
G
Appendino
Bernd
B
Nilius
Pierangelo
P
Geppetti
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology*; D004388:Dura Mater / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D039821:Monoterpenes; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014276:Trigeminal Nerve / Q000187:drug effects* / Q000378:metabolism; D027422:Umbellularia
D001643:Bridged Bicyclo Compounds; D003512:Cyclohexanones; D039821:Monoterpenes; D010936:Plant Extracts; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C557948:(1R,5S)-4-methyl-1-propan-2-ylbicyclo(3.1.0)hex-3-en-2-one; D015740:Calcitonin Gene-Related Peptide