Proton Activation Does Not Alter Antagonist Interaction with the Capsaicin-Binding Pocket of TRPV1

Vanilloid receptor 1 (TRPV1) is activated by chemical ligands and heat. In this study, we found that each of the group B antagonists competed with and prevented BCTC, AMG6880 or AMG7472 antagonism of rat TRPV1 activation by protons with pA2 values similar to those for blocking capsaicin, indicating that proton activation does not alter the conformation of the TRPV1 capsaicin-binding pocket. In conclusion, group A antagonists seem to lock the channel conformation in the closed state, blocking both capsaicin and proton activation.

Cluster headache pathogenesis, diagnosis, and management

Cluster headache is a stereotyped primary pain syndrome characterised by strictly unilateral severe pain, localised in or around the eye and accompanied by ipsilateral autonomic features. The syndrome is characterised by the circadian rhythmicity of the short-lived attacks, and the regular recurrence of headache bouts, which are interspersed by periods of complete remission in most individuals.

Cluster headache: pathogenesis, diagnosis, and management

Cluster headache is a stereotyped primary pain syndrome characterised by strictly unilateral severe pain, localised in or around the eye and accompanied by ipsilateral autonomic features. The syndrome is characterised by the circadian rhythmicity of the short-lived attacks, and the regular recurrence of headache bouts, which are interspersed by periods of complete remission in most individuals.

Sensing with TRP channels

Abstract
Drosophila melanogaster flies carrying the trp (transient receptor potential) mutation are rapidly blinded by bright light, because of the absence of a Ca2+-permeable ion channel in their photoreceptors. The identification of the trp gene and the search for homologs in yeast, flies, worms, zebrafish and mammals has led to the discovery of a large superfamily of related cation channels, named TRP channels. Activation of TRP channels is highly sensitive to a variety of chemical and physical stimuli, allowing them to function as dedicated biological sensors that are essential in processes such as vision, taste, tactile sensation and hearing.

A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a Novel and Selective Transient Receptor Potential Type V1 Receptor Antagonist, Blocks Channel Activation by Vanilloids, Heat, and Acid

The vanilloid receptor transient receptor potential type V1 (TRPV1) integrates responses to multiple stimuli, such as capsaicin, acid, heat, and endovanilloids and plays an important role in the transmission of inflammatory pain. Here, we report the identification and in vitro characterization of A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel, potent, and selective TRPV1 antagonist.

Headaches with (ipsilateral) autonomic symptoms

Primary short-lasting headaches broadly divide themselves into those associated with autonomic symptoms, so called trigemino-autonomic cephalgias (TACs), and those with little autonomic syndromes. The trigeminoautonomic cephalgias include cluster headache and paroxysmal hemicranias, in which head pain and cranial autonomic symptoms are prominent.

Cluster headache: ultrastructural evidence for mast cell degranulation and interaction with nerve fibres in the human temporal artery

It has been suggested that histamine plays an important role in the pathogenesis of cluster headache. In addition, both neurogenic and vascular components have been described during cluster headache attacks without an obvious anatomical link between them. Our ultrastructural observations of human temporal arteries from cluster headache patients and their comparison to those from a control group strongly suggest that mast cells may be this link.