Why do you itch? Yes, yes, that rash, those hives, sure. But what is that sensation? Why does scratching sometimes increase pain but reduce itch? Even more intriguing: why are drugs that treat the itch from a mosquito bite powerless against the itch that accompanies an effective and widely-used malaria treatment? The first step in answering these questions is to map the molecular route between your brain and the stimuli causing pain or itch. Discoveries at this molecular level are crucial for drug design and medical therapy. UC Berkeley molecular and cell biology professor Diana Bautista and her colleagues are exploring the molecules that function in the neural pathways behind itch and pain. Her research may someday mean that we can put all that nasty scratching behind us.
The sensation of itch, or pruritus, has traditionally been viewed as a milder form of pain, suggesting that both sensations are mediated by common chemical signals and pathways. Recent evidence challenges this long-standing model by supporting the idea that pain and itch are distinct sensations mediated by separate groups of neurons, or “lines” of communication to the brain. This theory better explains why vigorous scratching, which produces mild pain, can have an inhibitory effect on itch; chemicals released by the “pain line” can mask the effects of the “itch line.” In a recent paper published in Nature Neuroscience (Wilson et al. 2011), the Bautista lab reports that a particular neural ion channel called TRPA1 may bridge these two theories and provide a long-sought-after target for treating a variety of pains and itches.
TRPA1 is something of a gatekeeper in pain and itch signaling, acting in response to both pain and itch stimuli while residing in a subset of the neurons associated with itch. As an ion channel, TRPA1 operates at the cell membrane to transport positive cations for neuronal activation in response to different signals. In biological signaling, molecule A binds to a receptor that results in a signal to molecule B, which in turn activates C and so on. Molecules B and C are defined as “downstream” of A. Molecules and their receptors are often very specific, like a lock and key. Often, a single event like a mosquito bite results in a barrage of different A molecules that activate a variety of signaling pathways. “Most itch conditions involve more than one activating molecule (or molecule A)”, says Sarah Wilson, a graduate student in the department of Molecular and Cell Biology at UC Berkeley and the lead author on the paper. “Blocking one receptor [upstream] might inhibit some of the mosquito-bite itch, for example, but other itch signals can still get through.” So, targeting a single receptor is ineffective at stopping the wide variety of stimuli that can cause itch and pain. This is where TRPA1 comes in. In the pain and itch-signaling pathway, TRPA1 is found downstream of the receptors that initially signal irritation to the body. So when a mosquito bites, the sensation is not immediately relayed by TRPA1. This positioning is important because it means that many different itch and pain-causing chemicals all go through one gatekeeper, TRPA1. “Inhibiting TRPA1 will block many more of the signals relayed by a single bug bite, “ says Wilson.
The Bautista lab and other neurobiologists initially identified TRPA1 as a pain sensor, but they noticed that it is expressed in the dorsal root ganglion (DRG) – a fraction of neurons that also sense itch. The Bautista lab tested whether the TRPA1 ion channel plays a role in mediating itch using multiple techniques. First, they genetically engineered mice to lack TRPA1. Then, they isolated their DRG neurons and treated them with itch-inducing compounds: the malaria drug chloroquine (CQ) and an endogenous pruritogen (something produced naturally in your body to induce itch), BAM peptide. As compared to normal DRG neurons, those that lacked TRPA1 failed to activate in response to the compounds. To confirm their result, they injected the itch-inducing compounds into mice lacking TRPA1 and compared their behavior to normal mice. The normal animals respond to the injection by distinct, quantifiable scratching behaviors. However, mice lacking TRPA1 outwardly showed decreased responses to both compounds; when injected with them, the engineered mice did not scratch as furiously as their normal counterparts.
The Bautista lab’s discovery that TRPA1 acts not only as a pain sensor but also as an itch relay has far-reaching implications for drug design. Although treatments for the histamine-mediated mosquito-bite itch already exist in the form of anti-histamines, these drugs are like fighting only one platoon of an enemy’s army when attacked on multiple fronts. TRPA1 might be the key to a strategy for cutting off the enemy’s supply route and thus crippling all of its forces. “That’s why anti-histamines don’t always work,” says Bautista. “The same cells that release histamine also release BAM peptides, among many other compounds.” Further, itch sensations associated with chronic illnesses such as liver disease, atopic dermatitis, or side effects of CQ are all unaffected by anti-histamines. The Bautista lab’s discovery has the potential to make finding the specific pathways behind these chronic itch conditions unnecessary.
TRPA1 appears to be a specific and important target for drug design. Currently, the Bautista lab is working with Hydra Biosciences to test TRP channel inhibitors in mouse models that exhibit chronic itch. Encouragingly, inhibiting TRPA1 activity reduces both CQ and BAM-induced itch responses in mice, according to Bautista. In the future, they hope to have effective and specific treatments against chronic, intractable itch.