Sarah Ross, PhD
Associate Professor
Department of Neurobiology
University of Pittsburgh
(March 27, 2018)
The Neural Circuits of Itch and Pain
We all know the annoyance of scratching a mosquito bite, only to have the itching get worse. But what about an itch or pain that is felt for no apparent reason? These can be debilitating problems that lower quality of life. Doctor Ross is examining the neuronal basis for persistent itch and pain. She discussed her work using a mouse model to locate molecular signals that modulate the intensity of pain or itch at the spinal cord.
Persistent pain and itch are widespread, debilitating conditions for which there is a pressing need for more effective treatments. Our approach to address this important health issue is to gain a better understanding of the underlying neural circuits. Towards this the Ross lab developed a novel approach allowing the manipulation of defined subsets of neurons within the context of semi-intact somatosensory preparation that is responsive to mechanical, thermal, and chemical stimulation of the skin and from which they can identify and record from spinal output neurons.
They found that mice lacking the transcription factor Bhlhb5 show elevated itch, and that this effect is caused by the loss of a specific population of spinal inhibitory neurons during development, which they termed B5-I neurons. Ross lab research revealed that B5-I neurons differentiate into two neurochemically distinct subsets of neurons in adult mice: dynorphin and nNOS subsets, which are lost in the dorsal horn of Bhlhb5 mutant mice. Since 80% of B5-I neurons express dynorphin, they also analyzed the role of KOR signaling in itch. These studies revealed that KOR signaling bidirectionally modulates itch sensitivity within the spinal cord: increasing kappa tone decreases itch, whereas decreasing kappa tone increases itch. Finally, their work provides evidence that B5-I neurons inhibit itch both through direct inhibition of spinal projection neurons, as well as by presynaptic opioid-mediated inhibition via release of dynorphin. These findings suggest the cellular basis through which counter-stimulation mediates the inhibition of itch.
One of the salient features of pain following injury is that nociceptive input becomes amplified. Though the spinal cord is thought to play a key role in the amplification of nociception, the specific microcircuits involved are poorly understood. Wind-up is a physiological mechanism of sensory amplification that may, under pathological conditions, contribute to hypersensitivity and allodynia. Although it is clear that wind-up is a network phenomenon, few studies have addressed the nature of such a network. Ross showed that one-fifth of lamina I spinoparabrachial (SPB) neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory neurotensin-expressing interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain’s unpleasantness.