The role of NPY-containing inhibitory interneurons in spinal pain pathways

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Nerve fibres entering the spinal cord carry various types of sensory information to a region called the dorsal horn. Incoming sensory information is transmitted to a class of nerve cells called projection neurons, which convey it to the brain for conscious perception. However, the vast majority of nerve cells in the spinal cord are interneurons, which are responsible for local processing and modulation of sensory information before it reaches the projection neurons. Around a third of the interneurons release chemical messengers (neurotransmitters) that reduce the activity of other nerve cells, and therefore have an inhibitory function. These inhibitory interneurons control the flow of sensory information, including that which is perceived as pain. It is thought that a reduction of their activity contributes to some types of chronic pain, for example the pain that can occur after nerve injury. Despite the importance of the dorsal horn in pain mechanisms, we still know relatively little about the organisation of its nerve cells and circuits, or about how they process the incoming sensory information. This is largely because of the difficulty in defining specific functional populations among the interneurons. Work from our laboratory has shown that several different types of inhibitory interneuron can be recognised, based on the presence of specific chemical markers. One group consists of cells that make a substance called neuropeptide Y (NPY), and these account for around 15% of inhibitory interneurons in the superficial part of the dorsal horn and are scattered through its deeper part. Recent studies have selectively silenced or activated two other populations of inhibitory interneurons, and shown that these have different roles in reducing pain. From what we already know about the connections of the NPY cells, we predict that they will inhibit several different types of acute pain (but not itch), and that they will suppress chronic pain caused by inflammation or nerve injury. The main aim of this project is to test this hypothesis, and we will do this by using a strain of genetically altered mouse in which the NPY cells can be specifically targeted. We will make injections into the spinal cords of these mice of viruses that will either silence or activate these cells, while having no effect on other neurons. We will then test the prediction that inhibiting the NPY cells causes a reduction of pain thresholds, while activating them results in less pain following inflammation or nerve injury. We will verify that only NPY cells have been affected, and that we can therefore attribute any behavioural changes to an effect on these cells.Two different inhibitory neurotransmitters, GABA and glycine, are used by spinal cord interneurons, and we will test the predictions that the NPY cells in the superficial part of the dorsal horn use only GABA, and that they make synaptic connections with many other types of neuron in this region. This will be achieved with "optogenetics", in which light is used to activate specific populations of nerve cells. In addition, we will test whether the NPY cells in the deep part of the dorsal horn are also inhibitory interneurons, and find out which neurotransmitter they use.We will also use viral injections to visualise the NPY cells without altering their activity. In this way, we will find out more about the functions of a specific subset of these neurons, which strongly inhibit a particular group of projection neurons that respond to painful stimuli. We will test the prediction that they are activated by both tactile and painful stimuli, and therefore contribute to suppression of pain by touch, as well as setting a level of pain that is appropriate to the strength of the stimulus. These experiments will provide important insight into how inhibitory nerve cells in the spinal cord are involved in suppressing pain. This type of information is essential in the search for new analgesic drugs.