Neuronal circuits for itch in the spinal dorsal horn

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Chronic itch is a distressing condition that affects over 20% of the population. It is a feature of many diseases, including conditions affecting skin, kidneys and blood, as well as some types of cancer and HIV infection. It is also a side-effect of certain drugs, such as morphine. For most patients with chronic itch there are no satisfactory treatments, and a quarter of these patients suffer itch for more than 5 years. Despite its clinical importance, we have only a limited knowledge about the nerve circuits in the spinal cord and brain that are responsible for itch. Sensory information enters the spinal cord and is processed through complex circuits involving different types of local nerve cells (interneurons), before being carried to the brain by a type of nerve cell called a projection neuron. Many different types of spinal cord interneuron are involved in itch and pain pathways. Some of these (excitatory interneurons) transmit information through these circuits, while others (inhibitory interneurons) block the passage of information. Painful stimuli can powerfully suppress itch, which is why scratching provides temporary relief. We have identified a type of inhibitory interneuron in the spinal cord that reduces itch, and shown that these cells are responsible for the relief of itch by scratching. These inhibitory cells contain a peptide (a short protein) called dynorphin. Two different types of excitatory interneuron are thought to be part of the itch pathway. One of these contains a different peptide (gastrin-releasing peptide, or GRP) and the other possesses the receptor on which GRP acts (the GRP receptor, or GRPR).Recent studies have suggested a nerve circuit for transmitting itch, in which sensory fibres from the skin activate GRP cells, which then excite GRPR cells. Information from these is transmitted to the brain via itch-selective projection neurons. We have provided evidence that the inhibitory dynorphin cells reduce itch by blocking transmission at the level of the GRPR cells. In this project, we will test several components of the proposed circuit. We have already found that activating dynorphin cells reduces itch, but it is important to show that reducing their activity increases itch. We will also test whether their inhibitory action is selective for itch, or whether it also reduces pain. The GRP cells are known to receive input from one type of itch-sensitive nerve fibre. However, we recently identified a new class of nerve fibre that is likely to respond to different itch-inducing stimuli, and we will see whether these also target the GRP cells. The GRPR cells are already implicated in itch, because destroying them reduces itching without affecting pain. However, little is known about these cells. Our initial studies suggest that they correspond to a type of excitatory interneuron, known as vertical cells, which provide input to projection neurons, and we will carry out further studies to confirm this. We will determine the types of sensory input they receive, and whether they respond selectively to itchy (but not painful) stimuli. Most projection neurons in this region of the spinal cord carry pain signals, with a subset being activated by itchy stimuli. We will therefore see whether the GRPR cells only target the itch-activated projection neurons. We will also test the prediction that dynorphin cells block itch by inhibiting the GRPR cells, and we will identify the chemical messengers that they use. Finally, we will determine whether the GRPR cells are indeed critical and selective for itch, by increasing or decreasing their activity and testing the effects on itch and pain behaviour.The project will provide important new information about nerve circuits in the spinal cord that are involved in itch. Taken together with emerging information about the drug receptors that are present on different types of nerve cell, it should assist in the development of new treatments for chronic itch.