Dissecting the relative contributions of injured and intact primary afferents to neuronal plasticity and neuropathic pain

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Normal (nociceptive) pain is generated when specialised nerves (nociceptors) detect noxious stimuli and is a vital warning system that helps us to prevent or limit injury. Nociceptors send signals about the noxious stimuli to the spinal cord. Here, the signal is heavily modified before being transmitted to the brain, where the perception of pain is generated. Unlike nociceptive pain, neuropathic pain, which results from injury or disease of the nervous system, is a condition for which there is no known purpose. It affects over five million people in the UK alone and the majority of these patients are failed by current treatments and live in disabling pain.Neuropathic pain represents a dysfunction of pain transmission that can include spontaneous pain (stabbing or burning pain) and/or enhanced pain perception to both noxious and non-noxious stimuli (termed hyperalgesia and allodynia respectively). Changes in the way nociceptors and spinal circuits function are known to contribute to neuropathic pain. However, we know little about the precise nerves involved in different aspects of neuropathic pain, with the underlying causes of spontaneous pain a particularly understudied example. This is an incredibly important research area for two reasons. Firstly, because spontaneous pain is the major complaint from patients with neuropathic pain and, secondly, because knowing which nerves to target and where to do so, will be vital for the rational design of new drugs capable of ameliorating pain. It is clear from studies in patients that excessive electrical activity in nociceptors generates pain. Following injury to a nerve, injured nerves and intact neighbouring nerves develop spontaneous electrical activity; raising the question of how these two groups contribute to pain. This will be the central question of my research programme. To investigate, I will use a genetically altered mouse in which damaged and intact nerves are targeted separately with a protein capable of turning off electrical activity when a drug is given. I will use new behavioural methods to assess spontaneous pain in mouse models of neuropathic pain. The level of spontaneous pain when injured or intact nerves are switched off will be compared to give an insight into their respective contributions.While electrical activity in nociceptors is vital for spontaneous pain, the way the signal is processed in the spinal cord likely enhances or prolongs the pain experienced. Therefore, to study the changes that occur in the spinal cord, I will measure and compare the relative ease with which injured and intact nociceptors can activate spinal circuits. To visualise whether there are changes in spinal cord circuit structure following nerve injury, I will use genetically altered mice to label injured and intact nociceptors with different colours of fluorescent protein. In this way, I will be able to compare where these nerves go in the spinal cord and whether their connections with spinal nerves change after injury. These studies will be supported by recording from spinal nerves in tissue preparations while activating injured or intact nociceptors. By doing so, I will answer whether either pathway is strengthened following injury. Finally, I will study whether electrical activity in injured or intact nerves activates immune cells in the spinal cord, which are known to contribute to chronic pain. This will give us important information on whether activation of the immune system, independent of nociceptor electrical activity, should be an important consideration for drug development.This work will provide important information on the nerves involved in generating pain and how their activity can result in long-lasting and enhanced pain. In doing so, I will define new therapeutic targets that allow us to better design novel drugs for the treatment of neuropathic pain.