The molecular mechanisms of itchiness have left scientists scratching their heads for decades. Now, however, researchers have found a key piece of the circuitry that lets the body sense and respond to itchy irritations.
Based on experiments in mice, Hoon and his collaborator Santosh K. Mishra found that the itch sensation starts when the molecule natriuretic polypeptide B, or BNP, flows into a distinct set of nerve cells in the spinal cord. Those cells then send the itch signal up the central nervous system to the brain.
The results contrast with the previous theory that an itch is a low level form of pain and, therefore, uses the same molecules that help the body sense pain as well as changes in temperature. “Over the last 10 years, there’s been more evidence that that’s not the case,” Hoon said, referring to experiments showing that specific classes of neurons respond to specific stimuli, such as itch irritants.
But in the new study, the researchers have identified BNP as the switch that turns on the itchiness sensation. In addition, they have shown that the sensation is hardwired into the nervous system with its own unique biochemical circuit in the brain.
At first, the Hoon expected BNP to be linked to heat sensation or pain sensation rather than itchiness. But when he and Misra knocked down the BNP cell receptors in mice, the animals’ reactions to pain and heat stimuli were not affected. They then injected itch-inducing substances under the skin of both normal and BNP knockout mice. The normal mice scratched, but the knockout mice didn’t.
To track how BNP factors into an itch, the team targeted cells in the dorsal horn, an intersection in the spine where sensory signals from the body's periphery are routed to the brain. Using in situ hybridization to pinpoint the location of the BNP receptors, they determined that those receptors were only expressed in a subset of cells.
The researchers then poisoned that subset of cells in normal mice, effectively wiping out all BNP receptors. When exposed to an itch irritant, those mice scratched significantly less, while still responding normally to other sensory sensations, such as pain and touch. This confirmed that the cell receptors and BNP form a circuit specific to the itch sensation.
A previous study had shown that another receptor—gastrin-releasing peptide (GRP) receptor, or GRPR for short—was likely the primary transmitter of the itch sensation (2). But Hoon and Misra found little GRP expression in the cells where itch sensation begins. Instead, higher levels of GRP expression were found in the dorsal horn, suggesting that GRP acts after BNP in the itch sensation.
The cells and circuitry responsible for itching likely appear in humans too and could be good targets for the development of medications to deal with eczema, psoriasis, and other chronic itch conditions. But that might be problematic because the human heart makes and pumps BNP into the body to lower blood pressure. At the moment, it’s not clear whether regulating BNP in the spinal cord would have side effects on blood pressure and heart function. If that is the case, Hoon and Misra’s findings will help scientists identify other pieces of the itch pathway and target those instead.
- Mishra, S. and M. Hoon. 2013. The cells and circuitry for itch responses in mice. Science. 340: 968-971.
- Sun, Y.-G. G., Z.-Q. Q. Zhao, X.-L. L. Meng, J. Yin, X.-Y. Y. Liu, and Z.-F. F. Chen. 2009. Cellular basis of itch sensation. Science (New York, N.Y.) 325(5947):1531-1534.