Role of voltage-dependent calcium channels in nociceptive transmission under normal and neuropathic conditions

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This project seeks to increase our understanding of how living organisms function and behave and, also, to provide basic knowledge that can be used to develop new products for medicine. The basic knowledge here relates to how the function of specific proteins involved in nerve cell signalling may be affected in an animal model of disease. The proteins involved are called calcium channels and the disease that we model is pain caused by nerve damage. Everybody suffers from pain at some point in their lives, it is estimated that two-thirds of the elderly experience some form of pain on a daily basis. In fact, the costs of symptoms such as lower back pain are greater than heart disease, stroke and depression. Pain can arise from a variety of causes including injury, childbirth, headache, surgery or disease. Of course, pain is the body's warning system, vital to prevent us from prolonged exposure to harmful agents. Pain may be short-lived, disappearing when the cause is withdrawn, this type is usually called 'nociceptive' pain. However, longer-term or 'chronic' pain can arise from damage to nerves themselves, called 'neuropathic' pain. The real problem with neuropathic pain is that medicines that effectively treat nociceptive pain, such as common drugs like aspirin and even stronger painkillers like morphine, are largely ineffective. In fact, the major medicine for neuropathic pain, gabapentin, only works in about one-third of patients, and then only reduces the pain by around half. Therefore, it is clear that the quality of life in the UK would benefit from basic research into changes occurring during neuropathy, as ultimately this knowledge may lead to the introduction of much-need novel medicines. To address these issues, we will use a common animal model of neuropathy, which introduces injury by tying off spinal nerves. Once damage is established, we can monitor responses from the nerve cells that transmit messages to the brain alerting us of pain. A drug that successfully blocks these signals has the potential to treat neuropathic pain. Nerve cells communicate with their neighbours by releasing neurotransmitter substances. This release is controlled by calcium ions, which enter the cell via proteins called calcium channels. Using our animal model, we have applied a chemical isolated from tarantula spider venom which blocks a single class of calcium channels selectively. This chemical was found to reduce communication only in rats suffering from nerve damage, and not in non-injured rats. Therefore, if we were to give the same chemical to patients suffering neuropathic pain, their symptoms may be reduced. Of course, it may not be wise to give people a chemical found in the venom of a poisonous spider. However, chemists can make subtle changes to the structure of the chemical to make it safer (or more selective) if necessary. For instance, a similar chemical, which blocks a different type of calcium channel, has recently been developed and given approval to treat neuropathic pain. In addition to blocking calcium channels with drugs, we can also remove them genetically by 'knocking-out' the specific gene responsible for generating the channel. We can now see if responses are changed in animals that uniquely lack this particular calcium channel. We also want to find out the points in the pain signalling pathway where different calcium channels are important and, also, how these may be affected in our animal model. These studies will allow us to target particular channels selectively and avoid any side-effects of medication. By combining these techniques we will provide not only basic research, but may also contribute to knowledge about human medicine and healthcare that will improve quality of life in the UK.