Around 9% of the UK population live with neuropathic pain—chronic pain from nerve damage—and existing treatments often fail or cause severe side effects, as the opioid crisis has shown. This project investigates a specific protein, LGI1, that normally calms overactive spinal neurons. When LGI1 is missing or blocked, spinal neurons become hyperexcitable, amplifying pain signals and even spreading pain to uninjured areas. The researchers will use genetically altered mice and spinal cord recordings to identify exactly which neuron populations LGI1 controls, and through which molecular mechanisms (such as Kv1 channels and AMPA receptors). They will then test whether boosting LGI1 at the spinal level—using gene therapy or recombinant protein—can reverse pain behaviours in nerve-injured mice. If successful, this work could open a new avenue for treating neuropathic pain by targeting a specific, clinically relevant mechanism rather than broadly dampening the nervous system. Because LGI1 dysfunction is also linked to epilepsy, insights from this fundamental science may extend to other hyperexcitability disorders. The project does not promise an immediate therapy, but it aims to provide the mechanistic understanding needed to design more precise, less harmful pain treatments.
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Neuropathic pain, that is pain arising due to damage or disease of the somatosensory nervous system, remains a significant clinical problem affecting around 9% of the general population and is a major cause of disability worldwide. It not only negatively impacts an individual’s quality of life, but is a huge burden on healthcare services and detrimental to the economy and society as a whole. Unfortunately, current treatment options lack efficacy and result in severe side-effects, highlighted by the recent opioid crisis. It is understood that overactive neurons in the pain system underlie neuropathic pain which includes spinal neurons in the dorsal horn. Before signals are sent to the brain for the perception of pain, the spinal cord is a key site of sensory integration achieved through a network of heterogeneous populations of neurons. Following peripheral nerve injury, pathological changes occur within the spinal cord that lead to neuronal hyperexcitability and the loss of inhibitory control which are key in the worsening and maintenance of neuropathic pain. In order to develop better targeted and more effective therapies, it is paramount that we study the clinically relevant mechanisms which drive hyperexcitability within the pain system. Leucine-rich glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the central nervous system where a loss of its function leads to hyperexcitability disorders such as epilepsy. Autoantibodies against LGI1 are associated with neuropathic pain in patients. Pain in these patients can be relieved with therapies that block or reduce these antibodies showing that LGI1 disruption is a mechanism to cause neuropathic pain in the clinical setting. In line with this, we have preclinical data showing that genetic removal of LGI1 in the spinal cord of mice results in enhanced spinal neuron excitability, increased pain sensitivity, exacerbation of neuropathic pain behaviours and the spread of pain into uninjured regions. Therefore, the overarching aim of this project is to define the mechanisms by which LGI1 controls spinal neuron excitability particularly in the context of neuropathic pain, and assess the applicability of modulating this target at the spinal level for pain treatment. We will use genetically altered mice and electrophysiological recordings in the spinal cord to determine which specific neuron populations are regulated by LGI1 and understand the mechanisms by which LGI1 causes excitability changes (e.g. Kv1 channels, AMPA receptors). We will then specifically target these populations at the spinal level using a dual transgenic AAV approach in mice and assess the impact on acute and neuropathic pain. To test the therapeutic potential of modulation we will use AAVs for specific overexpression and recombinant LGI1 protein delivered to nerve injured mice. These findings will be of relevance to those researching the molecular mechanisms regulating spinal physiology in the normal and neuropathic conditions, as well as researchers exploring the role of LGI1 in other hyperexcitability disorders. Furthermore, new treatments for neuropathic pain will be hugely beneficial for society and have potential for use in other persistent pain conditions.
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