How Headache Tree Causes Cluster Headache and Migraine

in medicine, biology

Researchers have now identified the mechanism by which the plant California laurel, also known as headache tree, causes headache and migraine. They discovered that headache is caused when a bioactive compound released from the leaves of this plant triggers a cascade of chemical events in trigeminal nerves around head arteries. 

California laurel (Umbellularia californica, U. californica), a shrub indigenous to Northern California, is known by a host of common names, such as  pepperwood, spice tree and cinnamon bush, because of its strong aromatic properties and its alleged headache-inducing properties. Vapor from the aromatic leaves causes sinus irritation, sneezing and headache.

Umbellularia californica headache treeUmbellularia californica, the headache tree

Two years ago, Dr. Geppetti and coworkers, at the University of Florence in Italy, described the case of a gardener who suffered cluster headache for 20 years. Ten years after his last cluster headache attack, in three different occasions while pruning a California laurel he had a new cluster headache-like attack.  It was hypothesized that one or more molecules from the plant targeting the trigeminovascular system may cause migraine or cluster headache attacks.

The leaves of U. californica contain, as a major volatile constituent, monoterpene ketone umbellulone, a compound that, when administered to laboratory animals, produces irritating effects. Recently, the laboratory of Dr. Geppetti found that umbellulone specifically targets the transient receptor potential ankyrin 1 (TRPA1), an ion channel activated by mustard oil, cinnamon, wasabi and a series of endogenous reactive molecules, and expressed in a subset of trigeminal neurons which also express proinflammatory and vasodilatory neuropeptides.

 Umbellulone target TRPA1 trigeminal neuron mechanism
Umbellulone, by targeting TRPA1 on trigeminal neurons, causes neurogenic and CGRP-dependent vasodilatation. Image provided to by Dr Geppetti. 

In particular, one of these neuropeptides, the calcitonin gene-related peptide (CGRP), released from trigeminal terminals around intra and extracranial arteries, produces profound ‘neurogenic’ dilatation of these vessels. CGRP receptor blockade has been reported to ameliorate migraine attacks, probably by blocking the arterial vasodilatation produced by CGRP, and CGRP antagonists are considered novel medicines for migraine and cluster headache patients.  The observation that umbellulone, by targeting TRPA1 on trigeminal neurons, causes neurogenic and CGRP-dependent vasodilatation, suggests this pathway as the underlying mechanism of the headache caused by U. californica.  This conclusion is in line with another observation from Dr. Geppetti’s laboratory, which is that ethanol activates the capsaicin ‘receptor’ (TRPV1) (Trevisani et al. , 2002). TRPV1, which is co-expressed with TRPA1 within the same trigeminal neurons, releases CGRP and vasodilatation in meningeal and extracranial vessels  (Nicoletti et al. , 2008).

The mechanism identified in this study may explain why alcoholic beverages induce migraine and cluster headache attacks. Dr. Geppetti’s comment on this novel information is: “The mechanism, which eventually results in the throbbing and severe pain of migraine and cluster headache, still remains a mystery. However, we now know that the trigeminovascular system and CGRP release from trigeminal perivascular terminals and the resulting arterial vasodilatation play a major role in these conditions. Our previous and present findings contribute to the completion of the puzzle regarding the plethora of stimuli that trigger headache by discovering specific molecular targets that well-known headache triggers hit to activate neurogenic vasodilatation.”

Science Story Reference: 

The ‘headache tree’, via umbellulone and TRPA1, activates the trigeminovascular system. Nassini, R, Materazzi, S, Vriens, J, Prenen, J, Benemei, S, De Siena, G, la Marca, G, Andrè, E, Preti, D, Avonto, C, Sadofsky, L, Di Marzo, V, De Petrocellis, L, Dussor, G, Porreca, F, Taglialatela-Scafati, O, Appendino, G, Nilius, B, Geppetti, P (2011).  Brain. Epub ahead of print.

Additional Sources: 

1. Benemei, S, Appendino, G, Geppetti, P (2010). Pleasant natural scent with unpleasant effects: cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia 30: 744-6.

2. Ho, TW, Ferrari, MD, Dodick, DW, Galet, V, Kost, J, Fan, X, Leibensperger, H, Froman, S, Assaid, C, Lines, C, Koppen, H, Winner, PK (2008). Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372: 2115-23.

3. Nicoletti, P, Trevisani, M, Manconi, M, Gatti, R, De Siena, G, Zagli, G, Benemei, S, Capone, JA, Geppetti, P, Pini, LA (2008). Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig. Cephalalgia 28: 9-17.

4. Olesen, J, Diener, HC, Husstedt, IW, Goadsby, PJ, Hall, D, Meier, U, Pollentier, S, Lesko, LM (2004). Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350: 1104-10.

5. Trevisani, M, Geppetti, P, Davis, JB, Bianchi, A, Harrison, S, Randall, AD, Smith, GD, Owen, D, Brough, SJ, Jerman, JC, Gray, J, Amadesi, S, Campi, B, Barbieri, M, Tognetto, M, Gunthorpe, MJ, Smart, D (2002). Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5: 546-51.

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