Title

 

Authors

R. Nassini¹, G. De Siena¹, C. Avonto², G. Appendino², G. La Marca¹, P. Geppetti¹,S. Benemei¹ and S. Materazzi<sup>1

1</sup>Dept of Preclinical and Clinical Pharmacology and Headache Center, University of Florence, Italy; ²Dept of Chemical, Alimentary, Pharmaceutical and Pharmacological Sciences, University of Eastern Piedmont, Italy.

 

Abstract

Umbellularia californicaNutt., a tree indigenous to southwestern Oregon and Northern California, is known as ‛headache tree’ because its scent can trigger severe headache crises (Drake et al., 1935). The major volatile constituent of the leaves of U. californica, the monoterpene ketone, umbellulone, has irritating properties. However, the molecular bases underlying the headache-inducing properties of U. californica are unknown. The mechanisms of migraine and cluster headache are only partially understood. Activation of specific brain areas is proposed to activate the trigeminovascular system, and the subsequent release of calcitonin gene-related peptide (CGRP) from these nerves seems to play a prominent role in migraine and cluster headache attack (Goadsby et al., 1990). CGRP release from sensory nerve terminals results from the activation of multiple mechanisms, including some members of the transient receptor potential (TRP) family of channels. Peptidergic neurons are characterized by the expression of the capsaicin-sensitive vanilloid 1 (TRPV1) channel, and the mustard oil (MO)-sensitive ankyrin 1 (TRPA1) channel (Caterina et al., 1997). TRPA1 is also stimulated by cold temperatures, by a series of chemically diverse and highly reactive environmental agents, and by various electrophilic natural products that covalently modify cysteine residues of the channel (Jordt et al., 2004). This unusual activation is produced also by some endogenous mediators generated at sites of inflammation and tissue injury, including α,β-unsaturated aldehydes, 4-hydroxy-2-nonenal, acrolein and prostaglandins (Trevisani et al., 2007; Bautista et al., 2006; Materazzi et al., 2008)as well as other molecules. As the possible role of TRPA1 in trigeminal nerve function has been poorly explored, we investigated whether umbellulone may target the TRPA1 channel, and through this mechanism, cause nociceptive responses and CGRP release from trigeminovascular endings considered to be relevant to mechanisms of migraine. Umbellulone, from µM to sub-mM concentrations, selectively stimulated TRPA1-expressing HEK239 cells and rat trigeminal ganglion neurons, but not untransfected cells or neurons after TRPA1 blockade (HC-030031), and released CGRP from trigeminal nerve terminals. In wild type mice, but not in TRPA1 deficient mice, umbellulone excited cultured trigeminal neurons, released CGRP from sensory nerve terminals and caused nociceptive behavior after stimulation of trigeminal nerve terminals. Intranasal application or intravenous injection of umbellulone increased rat meningeal blood flow, a response that was selectively inhibited by systemic TRPA1 and CGRP receptor antagonists. Intranasal HC-030031 inhibited the response to a low  umbellulone dose (undetectable in plasma), but failed to affect the response to a high umbellulone dose (that yield high plasma levels, similar to that detected after intravenous administration). Homolateral trigeminal posterior rhizotomy also did not affect the response to the high dose of umbellulone. Collectively, these data suggest that both low-threshold-, TRPA1-dependent-, and higher threshold-, TRPA1-independent, mechanisms are involved in the obnoxious properties of umbellulone. The TRPA1-dependent ability of umbellulone to activate the trigeminovascular system, thereby causing nociceptive responses and CGRP release, represents a plausible mechanism for U. californica-induced headache.  

Drake et al. (1935) J Am Pharmaceut Assoc. 24:196-207
Goadsby et al. (1990) Ann Neurol. 28:183-7
Caterina et al. (1997) Nature. 389:816-24.
Jordt et al. (2004) Nature. 427:260-5
Materazzi et al. (2008) Proc Natl Acad Sci U S A. 105:12045-50.
Trevisani et al. (2007) Proc Natl Acad Sci U S A. 104:13519-24.
Bautista et al. (2006) Cell. 124:1269-82.