Itch (Latin: pruritus) is an important self-protection mechanism as well as annoying and often debilitating symptom of many skin and systemic conditions. The initial itch detection is carried out by a group of small-diameter sensory neurons in the trigeminal and dorsal root ganglia (DRG). Itch-sensing DRG neurons detect pruritogens through itch receptors on their peripheral axons in the skin and transmit signals to the spinal cord via their central axons. My research interests concern how primary sensory neurons detect itch-inducing stimuli (P1), how itch signals are encoded and transmitted in the nervous system (P2), and the molecular pathogenesis of chronic itching conditions (P3).
P1: To identify new itch receptors in the DRG
G protein-coupled receptors (GPCRs) play an important role in sensing chemical stimuli (chemosensation). Mas-related G protein-coupled receptors (Mrgprs) constitute a large family of GPCRs, which contains more than 50 members in mice. Many Mrgprs are specifically expressed by small-diameter DRG neurons in mice as well as in humans. The large Mrgpr family and their unique expression patterns led us to hypothesize that Mrgprs may be involved in the detection of diverse pruritogens and may provide molecular access to itch-sensing neurons. Using mouse genetic models and a combination of molecular, cellular, and behavioral techniques, we identified mouse MrgprA3 and human MrgprX1 as itch receptors and mediate the nonhistaminergic itch induced by chloroquine, a drug widely used to treat and prevent malaria but with serious pruritic side effects(Liu et al, Cell, 2009). Furthermore, our recent data reveal that MrgprC11 mediates itch induced by an opioid-related peptide BAM8-22 and an itch-inducing peptide SLIGRL (Liu et al, Science Signaling, 2011). The goal of this project is to extend these studies and test an interesting possibility of whether Mrgprs comprise a family of itch receptors and enable DRG neurons to detect various pruritogens.
P2: To dissect itch sensation
A long-standing debate in the itch field concerns how chemically diverse molecules induce a common sensation of itch. It is contentious whether different types of itch are perceived by distinct groups or by a common group of DRG neurons. Interestingly, MrgprA3 and MrgprC11 are co-expressed in a highly restricted subset of histamine-responsive cells in the DRG (4-5% of total DRG neurons), which mediate both histaminergic and nonhistaminergic itch through different receptors. However it is unlikely that the itch sensation is mediated exclusively by these fibers. Previous studies have shown that itch can be provoked by mechanical and electrical stimuli that are not likely to activate histamine-sensitive fibers. Furthermore, tropical legume cowhage, which induces strong nonhistaminergic itch in both humans and animals, robustly activates a population of histamine-insensitive C fibers. All of these hint at the existence of histamine-independent itch sensing fibers. But having no molecular markers for them impedes further study at cellular and molecular levels. My recent studies have identified a new population of histamine-independent itch sensing neurons. The goal of this project is to define the involvement of these two different itch populations in different types of itch and study their downstream signaling.
P3: To investigate the involvement of Mrgprs and their ligands in chronic itching conditions
For many chronic, nonhistaminergic itching conditions, the most painstaking challenge is to identify the major itch mediators and corresponding receptors. Lack of this information is the main reason for lack of treatment for these diseases. With genetic and molecular tools, we recently found that Mrgprs are involved in two chronic itch models. The primary goal of this project is to investigate the underlying mechanisms and develop new treatment strategies. These studies will potentially advance our understanding of the causes and mechanisms of chronic itch. In addition to current models, the involvement of Mrgprs and their ligands in other itching conditions will also be studied, with the hope of finding novel therapeutic targets for chronic itch.