Molecular and functional studies of mechanisms that determine the efficacy of anti-hyperalgesic agents in persistent pain models.

Pain is something we all experience in everyday life. It serves as a warning and survival message telling us of a threat to our body. Even the most primitive organisms such as slugs, snails and flies have mechanisms in their tiny nervous systems that allow them to escape damaging stimuli. Most of us have short-lasting pains but imagine that a headache, sprained ankle or period pain just went on and on and lasted for months and years on end. This is chronic pain. This chronic pain can arise from cancer, surgery, diseases such as rheumatism and arthritis and most people have a relation or know someone who has severe pain. This ongoing pain has a major impact on quality of life, disrupting social life, work, hobbies and furthermore, treatment can often be difficult. Nerves tell us what is happening in our bodies and in the outside world and by electrical and chemical events these messages are based on through our nervous system to the brain. If damage occurs to our visual system , our ability to see properly is lost and we may go blind. It is surprising how often our sensory nerves, nerves that signal pain and touch can be damaged. Examples could be an injury or even quite simple surgery. It is common that diseases such as diabetes, HIV and other viruses can lead to nerve damage. Most patients with damaged nerves have a loss of normal feeling and have numb areas. Remarkably, many patients also have severe and strange pains even though they have lost normal nerve function. One example would be phantom limbs where even through a part of the body has been removed by amputation, the person still 'feels' pain from the missing limb. Up to 25% of patients have severe and abnormal pains after nerve injury, leading to almost a million people in the UK. Pains from nerve injury include ongoing pain, allodynia, a very distressing state where mere touch or brushing is painful (patients often cannot bear the pressure of clothes or bedding, can't brush their hair) or hyperalgesia, (where a painful stimulus is many times worse than normal). These suggest the nervous system has been changed by the nerve injury. We want to find out what has happened in the nerves, spinal cord and brain to produce these abnormal pains. Patients with these pains not unexpectedly, often are depressed, anxious and can't sleep well. We have shown that the parts of the brain that deal with these emotions also change pain signals. How do these nervous pathways talk to each other and why do they change when nerves are damaged. A drug, gabapentin, (GBP) is the main treatment for nerve injury pain but it only works well in 1 in 3 patients and has no effect on ordinary pains. We want to find out why this is the case and understand how it only changes abnormal activity such as that caused by nerve injury. A chemical messenger in the brain called 5HT, important in mood and sleep, may be a key to the injury-linked pain reducing actions of gabapentin. Therefore this application will bring together 3 applicants using a wide range of modern techniques to understand how our nervous system is changed by external events such as pain and how and why drugs work. Knowledge of what determines this should allow greater numbers of patients to gain relief from this distressing pain state. It should enable us to understand how our nerves, spinal cord and brain have the ability to change the way they respond and interact in response to external stimuli, internal thoughts and disease states.

We aim to examine how peripheral nerve injury and other pains change neuronal signalling. Neuropathic pain is a common distressing condition where patients have severe and abnormal pains. Gabapentin (GBP), the first line treatment, binds to a unique site on two of the four alpha-2delta subunits (alpha-2delta -1 and alpha-2delta -2) of voltage-gated calcium channels (VGCCs), an auxiliary subunit common to all high VGCC subtypes. GBP is clinically effective and reduces abnormal pain behaviours such as allodynia and hyperalgesia in a range of animal models of persistent pain. However, it has no effect in healthy human volunteers or on noxious behavioural or neuronal responses in naive animals. We will investigate the cellular mechanism for the state-dependent actions of GBP in integrated systems, and test the hypothesis at the single cell and sub-cellular levels. Our recent studies have demonstrated that block of the 5-hydroxytryptamine type 3 receptor (5HT3R) attenuates noxious transmission, and that the role of 5HT acting on this receptor is enhanced by nerve injury. Preliminary data suggest that blockade of spinal 5HT3R prevents actions of GBP in neuropathic rats. GBP attenuates afferent transmitter release and the drug profile suggests a pre-synaptic action. We will use in vivo systems, in vitro electrophysiology and co-immunoprecipitation to ascertain whether a functional or physical interaction exists between 5HT3R (localised pre-synaptically) and VGCCs. This interaction, potentially mediated by the alpha-2delta subunit, may explain GBP's state dependency. This application brings together 3 applicants using molecular, in vitro mechanistic studies and in vivo studies to test these interactions within integrated systems.Knowledge of what determines the analgesic action of GBP should allow greater numbers of patients to gain relief, provide new targets for industry and improve understanding of how the nervous system responds to external and internal events.