A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch

Abstract

Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch.

Introduction

Itch is a multidimensional sensory experience that all human beings experience in the course of their lives (Yosipovitch, 2004). From a neurophysiological perspective, two distinct peripheral and spinothalamic pathways have been discovered for itch: a histaminergic pathway and a non-histaminergic pathway mediated by proteinase activated receptors 2, PAR2 (Steinhoff et al., 2003). The latter is activated exogenously by the spicules of cowhage, a tropical plant which represents a particularly valuable experimental itch inducer (Papoiu et al., 2011). Upon skin contact, cowhage spicules release mucunain, a cysteine protease that serves as a ligand for the PAR2 receptors (Reddy et al., 2008) and elicits a strong sensation of “itch without a flare” that lasts for several minutes (LaMotte et al., 2009, Sikand et al., 2009). Current reports suggest that PAR2 mediated itch may be a more appropriate model for pathological pruritus than models based on histamine, since antihistamines are not effective in clinical practice as antipruritics. PAR2 receptors have been shown to play a role in itch of atopic eczema (Steinhoff et al., 2003). While brain processing of histamine-induced itch has been investigated in several studies (Darsow et al., 2000, Drzezga et al., 2001, Hsieh et al., 1994, Leknes et al., 2007, Mochizuki et al., 2003, Mochizuki et al., 2009, Pfab et al., 2010, Schneider et al., 2008, Valet et al., 2008, Vierow et al., 2009) no studies have yet investigated the brain processing of cowhage-induced itch. The peripheral afferent C-nerve fibers conveying cowhage-induced itch are separate from the pathway stimulated by histamine itch (Johanek et al., 2007, Namer et al., 2008) and the subsequent spinothalamic routes are also distinct (Davidson et al., 2007, Davidson et al., 2009; reviewed in Davidson and Giesler, 2010). Little is known about the projections of these two itch specific pathways to their superior end-processing stations in the cerebral cortex; therefore, brain imaging offers a useful methodology to track these two distinct itch pathways towards their final destination. In the current study, we analyzed and contrasted the cerebral representation of itch induced by these two distinct modalities, histamine and cowhage, as well as the effect of the simultaneous activation of both pathways, to gain insight into their central processing. We employed Arterial Spin Labeling (ASL), a suitable technique to capture long-term changes in cerebral perfusion that parallel the extended duration of itch (Ishiuji et al., 2009). It is of notable interest to describe the brain networks involved in the processing of itch and examine if these two forms of itch have a distinct representation in the brain, especially since cowhage itch is a promising model for chronic itch of pathological origin in humans.