The itch sensation is triggered by two categories of itch-inducing agents: histamine (involving the histamine receptor) and non-histamine (involving a Mas-like G-protein coupled receptor). While the molecular distinction is crucial for developing effective treatments for the specific forms of itch sensation, it remains unclear as to how the two forms of itch sensations are encoded in the sensory system. A heavily debated school of thought suggests that itch sensation, in response to either histamine and non-histamine inducers, is differentially triggered by distinct populations of sensory neurons, although such model has never been proven.

In a recent publication in Nature Neuroscience (Roberson et al., May 19, 2013, doi:10.1038/nn.3404), the authors proved for the first time that distinct populations of sensory neurons (dubbed pruriceptors) are involved in encoding histamine and non-histamine induced itch. The authors did so by using an ingenious method to silence specific populations of sensory neurons using a cell-impermeable form of lidocaine, a sodium channel inhibitor that suppresses the electrical activity in neurons. This drug, QX-314, is designed to enter neurons exclusively via large pore ion channels that are specifically activated either by histamine or non-histamine itch inducers. To suppress the activity of histamine-responsive pruriceptors, for example, scientists can easily do so by treating sensory neurons with a combination of QX-314 with histamine, allowing QX-314 to enter the specifically histamine-responsive neurons via their histamine-responsive pore ion channel, silencing only the histamine pruriceptors. The suppression of non-histamine pruriceptors can likewise be achieved by treating sensory neurons with a combination of QX-314 with non-histamine itch inducers (ex: chloroquine), allowing QX-314 to selectively enter and silence only the non-histamine pruriceptors. The authors showed that blockade of histamine pruriceptors blocked only histamine-induced itch, and not chloroquine-induced itch. Likewise, blockade of non-histamine pruriceptors blocked only chloroquine-induced itch, and not histamine-induced itch. 

The authors further discovered that although pruriceptors are not involved in pain perception, these neurons still express pain receptors that are apparently crucial for evoking a scratch response. The authors further found that TRPV1 (capsaicin-responsive) and TRPA-1 (AITC-responsive) pain receptors are differentially expressed in pruriceptors, with the first expressed primarily by histamine pruriceptors, and the latter by the non-histamine pruriceptors.  The selective silencing of TRPV1 or TRPA1 expressing neurons can suppress the animal’s scratch response to histamine and non-histamine itch, while evoking an abnormal itch response to capsaicin and AITC. This suggests that the pain receptors are involved in masking itch sensation, augmenting itch response to common itch-inducers, while suppressing the itch response to pain-inducers. The discovery reveals, for the first time, the elusive role of pain receptors in controlling itch response.

The author’s work is an important advance in understanding the neural networks encoding histamine and non-histamine induced itch sensations, and how pain receptors modulate itch sensation. The study provides the first functional evidence supporting that different populations of sensory neurons are involved in encoding histamine and non-histamine induced itch sensation, although some overlap is observed in in vivo cases. By showing the precise population of sensory neurons responsible for distinct itch signals, the study creates the first functional map on which future experiments (using optogenetics) can ensue to further elucidate the neuroscience underlying itch perception in rodents. Moreover, by showing the pivotal role of pain receptors in controlling itch response to various inducers, the study has important implications on whether pain receptor antagonists could have undesired “itchy” consequences.

Lastly, as chronic itch can be a debilitating problem in a number of medical conditions, this study has far-reaching applications in medicine. By enabling scientists to elucidate the precise origin of itch sensation in sensory neurons, treatments can be developed to alleviate specific types of itch sensations by targeting the relevant sensory neurons.