Pain, itch, gentle touch. These three vastly different sensations all start from the same place—a bundle of nerves at the base of the spine known as the dorsal root ganglion. At the Johns Hopkins University School of Medicine, neuroscientist Xinzhong Dong is uncovering the molecular and cellular basis of all three, with an eye toward better treatments for chronic pain and itch.
Dong’s interest in biology began early on, with almost daily trips with his father to the zoo in Beijing. He spent summer days digging up cicada nymphs that had burrowed underground and watching their metamorphosis from pupa to adult. Today he studies the inner workings of sensory neurons.
Dong first began studying sensory biology as a postdoctoral fellow at the California Institute of Technology. In the lab of HHMI investigator David Anderson, Dong searched for genes that were expressed only in sensory nerves, expecting they would likely have important roles in those cells. He identified genes responsible for a family of about 50 protein receptors, known as Mrg receptors, that are expressed in mice only in dorsal root ganglion neurons. “We were really excited about the discovery of these genes,” he says. “But for a long time we didn’t really know what these genes do, except that they are highly specifically expressed in dorsal root ganglia.”
In his Hopkins lab, Dong is uncovering the function of these genes by combining genetic and behavioral studies in mice with electrophysiology, biochemistry, and molecular biology to reveal how signals triggered by the Mrg receptors are processed as they travel from the skin to the spinal cord.
His recent studies have shown that these receptors play a role in certain kinds of itch sensations. In some people, the antimalarial drug chloroquine causes an extremely unpleasant itching that is not relieved by antihistamine medications. The itching can be so intense that many people stop taking the drug. Normal mice that receive chloroquine react similarly to humans, but mutant mice lacking certain Mrg receptors show a drastic reduction in scratching behavior. These mice seem to be immune to chloroquine’s itch-inducing side effects.
On the basis of these studies, Dong determined that a small subset of dorsal root ganglion neurons is dedicated to itch sensation. Now he can perform experiments to visualize where the neurons begin and end and which neurons they send signals to in the spinal cord. He intends to examine the effects of genetically removing them in mice.
Dong is also pursuing the relationship between itch and pain sensations. Some pain relievers, such as morphine, can have itchy side effects. And the pain caused by scratching can make an itch subside, at least temporarily. This antagonistic relationship is not well understood, but Dong hopes that a better understanding of the sensory pathways will illuminate where this effect occurs.
He is working on several projects to identify and describe the pain pathways and hopes to find new drugs for treating chronic pain. “We really need a novel and specific drug target,” he says. He has observed that activating one of the Mrg receptors can inhibit chronic pain in mice and causes no visible problems. “The specificity of these genes makes them great candidates for drug development because it minimizes side effects,” unlike most commonly used medications for chronic pain, Dong says.
Gentle touch, his third area of research, is perhaps the least understood. Preliminary studies suggest that one Mrg gene, which is expressed in a small subset of dorsal root ganglion neurons, might be involved in perceiving gentle touch. If his experiments confirm that these neurons detect gentle touch, he wants to explore how that sensation provokes feelings of comfort and pleasure in the brain.